Tugas Hipoglikemia pada Neonatus - Pediatri Banjar 2014

HIPOGLIKEMIA PADA NEONATUS

Oleh Rifa Imaroh 2010730092

Hipoglikemi  adalah  keadaan hasil pengukuran kadar glukosa darah kurang dari 45 mg/dL (2.6 mmol/L). Hipoglikemia adalah masalah metabolik paling umum pada neonatus. Pada anak-anak, sebuah glukosa darah nilai kurang dari 40 mg / dL (2,2 mmol / L) merupakan hipoglikemia. Sebuah glukosa plasma tingkat kurang dari 30 mg / dL (1,65 mmol / L) dalam 24 jam pertama kehidupan dan kurang dari 45 mg / dL (2,5 mmol / L) setelahnya merupakan hipoglikemia pada bayi baru lahir.

Pasien dengan hipoglikemia mungkin asimtomatik atau mungkin dengan gangguan sistem saraf pusat (SSP) yang parah dan cardiopulmonary. Manifestasi klinis yang paling umum dapat mencakup tingkat kesadaran yang berubah, kejang, muntah, unresponsiveness, dan kelesuan. Setiap anak sakit harus dievaluasi untuk hipoglikemia, terutama ketika anamnesis mengungkapkan asupan oral berkurang.

Hipoglikemia berkelanjutan atau berulang pada bayi dan anak-anak memiliki dampak yang besar pada perkembangan otak normal dan fungsi. Bukti menunjukkan bahwa hipoksemia dan iskemia berpotensi terjadi hipoglikemia, menyebabkan kerusakan otak yang permanen dapat mengganggu perkembangan neurologis.

Etiologi

Penyebab hipoglikemia pada neonatus berbeda sedikit dari pada bayi yang lebih tua dan anak-anak. Penyebab pada neonatus meliputi berikut:

§  Perubahan sekresi hormon

§  Berkurangnya Substrat cadangan dalam bentuk glikogen hati

§  Berkurangnya cadangan Otot sumber asam amino untuk glukoneogenesis

§  Berkurangnya cadangan Lipid  untuk pelepasan asam lemak

Patofisiologi

§  Hipoglikemi sering terjadi pada  BBLR, karena cadangan glukosa rendah.

§  Pada ibu DM terjadi transfer glukosa yang berlebihan pada janin sehingga respon insulin juga meningkat pada janin. Saat lahir di mana jalur plasenta terputus maka transfer glukosa berhenti sedangkan respon insulin masih tinggi (transient hiperinsulinism) sehingga terjadi hipoglikemi.

§  Hipoglikemi adalah masalah serius pada bayi baru lahir, karena dapat menimbulkan kejang yang berakibat terjadinya hipoksi otak. Bila tidak dikelola dengan baik akan menimbulkan kerusakan pada susunan saraf pusat bahkan sampai kematian.

§  Kejadian hipoglikemi lebih sering didapat pada bayi dari ibu dengan diabetes melitus.

§  Glukosa merupakan sumber kalori yang penting untuk ketahanan hidup selama proses persalinan dan hari-hari pertama pasca lahir.

§  Setiap stress yang terjadi mengurangi cadangan glukosa yang ada karena meningkatkan penggunaan cadangan glukosa, misalnya pada asfiksia, hipotermi, hipertermi, gangguan pernapasan.

Diagnosis

Presentasi klinis hipoglikemia mencerminkan penurunan ketersediaan glukosa untuk SSP serta stimulasi adrenergik disebabkan oleh tingkat darah menurun atau rendah gula. Selama hari pertama atau kedua kehidupan, gejala bervariasi dari asimtomatik ke SSP dan gangguan cardiopulmonary. Kelompok berisiko tinggi yang membutuhkan skrining untuk hipoglikemia pada satu jam pertama kehidupan meliputi

§  Bayi yang baru lahir yang beratnya lebih dari 4 kg atau kurang dari 2 kg

§  Besar usia kehamilan (LGA) bayi yang berada di atas persentil ke-90, kecil untuk usia kehamilan (SGA) bayi di bawah persentil ke-10, [4] dan bayi dengan pembatasan pertumbuhan intrauterin

§  Bayi yang lahir dari ibu tergantung insulin (1:1000 wanita hamil) atau ibu dengan diabetes gestasional (terjadi pada 2% dari wanita hamil)

§  Usia kehamilan kurang dari 37 minggu

§  Bayi yang baru lahir diduga sepsis atau lahir dari seorang ibu yang diduga menderita korioamnionitis

§  Bayi yang baru lahir dengan gejala sugestif hipoglikemia, termasuk jitteriness, tachypnea, hypotonia, makan yang buruk, apnea, ketidakstabilan temperatur, kejang, dan kelesuan

§  Selain itu, pertimbangkan skrining hipoglikemia pada bayi dengan hipoksia yang signifikan, gangguan perinatal, nilai Apgar 5 menit kurang dari 5, terisolasi hepatomegali (mungkin glikogen-penyimpanan penyakit), mikrosefali, cacat garis tengah anterior, gigantisme, Makroglosia atau hemihypertrophy (mungkin Beckwith-Wiedemann Syndrome), atau kemungkinan kesalahan metabolisme bawaan atau ibunya ada di terbutalin, beta blocker, atau agen hipoglikemik oral

§  Terjadinya hiperinsulinemia adalah dari lahir sampai usia 18 bulan. Konsentrasi insulin yang tidak tepat meningkat pada saat hipoglikemia didokumentasikan. Hiperinsulinisme neonatal Transient terjadi pada bayi makrosomia dari ibu diabetes (yang telah berkurang sekresi glukagon dan siapa produksi glukosa endogen secara signifikan dihambat). Secara klinis, bayi ini makrosomia dan memiliki tuntutan yang semakin meningkat untuk makan, lesu intermiten, jitteriness, dan kejang jujur.

Bayi dengan hiperinsulinisme neonatal berkepanjangan dapat digambarkan sebagai berikut:

§  SGA

§  Memiliki asfiksia perinatal

§  Lahir dari ibu dengan toksemia

§  Memiliki tingkat penggunaan glukosa dan sering membutuhkan infus dextrose untuk jangka waktu lama

§  Hipoglikemia ketotik merupakan suatu penyakit, jarang, tapi dramatis. Hal ini diamati pada anak-anak muda dari usia 5 tahun, yang biasanya menjadi gejala setelah puasa semalam atau berkepanjangan, terutama dengan penyakit dan asupan mulut yang buruk. Anak-anak sering hadir sebagai misterius lesu atau terus terang koma, setelah hanya ditandai dengan hipoglikemia ketonuria.

Anamenesis

§  Riwayat bayi  menderita asfiksia, hipotermi, hipertermi, gangguan pernapasa

§  Riwayat bayi prematur

§  Riwayat bayi Besar untuk Masa Kehamilan (BMK)

§  Riwayat bayi Kecil untuk Masa Kehamilan (KMK)

§  Riwayat bayi dengan ibu Diabetes Mellitus

§  Riwayat bayi dengan Penyakit Jantung Bawaan

§  Bayi yang beresiko terkena hipoglikemia

§  Bayi dari ibu diabetes (IDM)

§  Bayi yang besar untuk masa kehamilan (LGA)

§  Bayi yang kecil untuk masa kehamilan (SGA)

§  Bayi prematur dan lewat bulan

§  Bayi sakit atau stress (RDS, hipotermia)

§  Bayi puasa

§  Bayi dengan polisitemia

§  Bayi dengan eritroblastosis

§  Obat-obat yang dikonsumsi ibu, misalnya sterorid, beta-simpatomimetik dan beta blocker

Pemeriksaan Fisik

§  Manifestasi klinis yang luas dan dapat hasil dari stimulasi adrenergik atau dari penurunan ketersediaan glukosa untuk SSP. Tidak seperti anak-anak, bayi tidak dapat memverbalisasi gejala mereka dan sangat rentan terhadap hipoglikemia.

§  Bayi pada hari pertama atau kedua kehidupan mungkin asimtomatik atau memiliki mengancam jiwa SSP dan gangguan cardiopulmonary. Gejala dapat meliputi: hpotonia, lesuan, apatis, malas minum, kejang, gagal jantung kongestif, sianosis, apnea, hipotermi

§  Manifestasi klinis yang terkait dengan aktivasi sistem saraf otonom meliputi: Kecemasan, tremulousness, Diaphoresis, takikardi, anemia, mual, dan muntah

§  Manifestasi klinis dari hypoglycorrhachia atau neuroglycopenia meliputi:Sakit kepala,Mental kebingungan, menatap, perubahan perilaku, sulit berkonsentrasi

§  Gangguan visual (misalnya, penurunan ketajaman, diplopia), Dysarthria, kejang, Ataksia, mengantuk, koma, stroke(hemiplegia, aphasia), parestesia, pusing, amnesia, decerebrate atau mengulit sikap

Manifestasi klinis

§  jittery

§  keringat dingin

§  letargi

§  distress nafas

§  Sianosis

§  Kejang atau tremor

§  Letargi dan menyusui yang buruk

§  Apnea atau henti napas

§  Tangisan yang lemah atau bernada tinggi

§  Hipotermia

§  RDS

Diagnosis banding

§  Insufisiensi adrenal

§  Kelainan jantung

§  Gagal ginjal

§  Penyakit SSP

§  Sepsis, asfiksia

§  Abnormalitas metabolik (hipokalsemia, hiponatremia, hipernatremia, hipomagnesemia, defisiensi piridoksin).

§  Fasting

§  Malnutrition

§  Diarrhea

§  Enzymatic defects of glycogen synthetic pathways

§  Enzymatic defects of glycogenolytic pathways

§  Enzymatic defects of gluconeogenic pathways

§  Glucagon deficiency

§  Congenital hyperinsulinism (eg, nesidioblastosis, leucine sensitive hypoglycemia)

§  Defects of beta cell regulation

§  Large tumors

§  Decreased or absent fat stores

§  Enzymatic defects in fatty acid oxidation

Penyulit

§  Hipoksia otak

§  Kerusakan sistem saraf pusat

Tatalaksana

§  Monitor Pada bayi yang beresiko (BBLR, BMK, bayi dengan ibu DM) perlu dimonitor dalam 3 hari pertama : Periksa kadar glukosa saat bayi datang/umur 3 jam. Ulangi tiap 6 jam selama 24 jam atau sampai pemeriksaan glukosa normal dalam 2 kali pemeriksaan. Kadar glukosa ≤  45 mg/dl atau gejala positif tangani hipoglikemia

§  Pemeriksaan kadar glukosa baik, pulangkan setelah 3 hari penanganan hipoglikemia selesai

§  Hipoglikemia harus diperlakukan sesegera mungkin untuk mencegah komplikasi kerusakan neurologis. Awal makan bayi yang baru lahir dengan ASI atau susu formula dianjurkan. Bagi mereka yang tidak mampu untuk minum, selang nasogastrik dapat digunakan. Andalan terapi untuk anak-anak yang waspada dengan perlindungan jalan nafas utuh termasuk jus jeruk pada 20 mL / kg.

§  Bagi mereka yang tidak bisa melindungi jalan napas mereka atau tidak dapat minum, rute nasogastrik, intramuskular, intraosseous, atau IV dapat digunakan untuk obat berikut digunakan untuk meningkatkan kadar glukosa: dekstrosa, glukagon, diazoxide, dan octreotide. Laporan kasus telah menunjukkan bahwa nifedipin dapat membantu untuk mempertahankan normoglikemia pada anak dengan PHHI.

§  Kortisol tidak boleh digunakan, karena memiliki manfaat akut minimal dan dapat menunda diagnosis penyebab hipoglikemia. Kortisol merangsang glukoneogenesis dan menyebabkan penurunan penggunaan glukosa, yang mengarah ke peningkatan glukosa darah secara keseluruhan dan dapat menutupi penyebab sebenarnya dari hipoglikemia.

Anti-hipoglikemik : Obat ini meningkatkan kadar glukosa darah

§  Dekstrosa Dextrose adalah pengobatan pilihan. Hal ini diserap dari usus, mengakibatkan peningkatan pesat dalam kadar glukosa darah bila diberikan secara oral. Berikan IV dekstrosa untuk bayi dari ibu diabetes dengan hiperinsulinemia neonatal sementara selama beberapa hari sampai hiperinsulinemia mereda. Hindari hiperglikemia membangkitkan pelepasan insulin cepat, yang bisa menyebabkan hipoglikemia rebound. Bayi SGA dan mereka dengan toksemia ibu atau asfiksia perinatal memerlukan tingkat dextrose infus IV lebih dari 20 mg / kg / menit untuk mengontrol tingkat. Pengobatan mungkin diperlukan untuk 2-4 minggu.

§  Diazoxide (Proglycem) Diazoxide meningkatkan glukosa darah dengan menghambat pelepasan insulin pankreas dan mungkin melalui efek extrapancreatic. Efek hiperglikemia dimulai dalam waktu satu jam dan biasanya berlangsung maksimal 8 jam dengan fungsi ginjal normal. Diazoxide dilaporkan efektif pada bayi SGA dan pada mereka dengan toksemia ibu atau asfiksia perinatal.

§  Octreotide (Sandostatin)Octreotide adalah analog long-acting dari somatostatin yang menekan sekresi insulin untuk pengelolaan jangka pendek hipoglikemia.

§  Glukagon (Glukagon Darurat Kit, GlucaGen) Glukagon dapat digunakan untuk mengobati hipoglikemia sekunder untuk hiperinsulinemia dan dapat diberikan kepada pasien tanpa akses IV awal. ML masing-masing berisi 1 mg (yaitu, 1 U). Konsentrasi glukosa maksimal terjadi antara 5-20 menit setelah pemberian IV dan sekitar 30 menit setelah intramuskular (IM) administrasi.

§  Penanganan hipoglikemia dengan gejala :

ü  Bolus glukosa 10% 2 ml/kg pelan-pelan dengan kecepatan 1 ml/menit

ü  Pasang jalur iv D10 sesuai kebutuhan (kebutuhan infus glukosa 6-8 mg/kg/menit).
Contoh : BB 3 kg, kebutuhan glukosa 3 kg x 6 mg/kg/mnt = 18 mg/mnt = 25920 mg/hari. Bila dipakai D 10% artinya 10 g/100cc, bila perlu 25920 mg/hari atau 25,9 g/hari berarti perlu 25,9 g/ 10 g x 100 cc= 259 cc D 10%/hari.

§  Atau cara lain dengan GIR

Konsentrasi glukosa tertinggi untuk infus perifer adalah 12,5%, bila lebih dari 12,5% digunakan vena sentral. Untuk mencari kecepatan Infus glukosa pada neonatus dinyatakan dengan GIR.

Kecepatan Infus (GIR) = glucosa Infusion Rate

GIR (mg/kg/min) = Kecepatan cairan (cc/jam) x konsentrasi Dextrose (%)

                                                                6 x berat (Kg)

Contoh : Berat bayi 3 kg umur 1 hari

Kebutuhan 80 cc/jam/hari  = 80 x 3 = 240 cc/hari  = 10 cc/jam

GIR = 10 x 10 (Dextrose 10%) = 100 = 6 mg/kg/min

                             6 x 3                  18

ü  Periksa glukosa darah pada : 1 jam setelah bolus dan tiap 3 jam

ü  Bila kadar glukosa masih < 25 mg/dl, dengan atau tanpa gejala, ulangi seperti diatas

§  Bila kadar 25-45 mg/dl, tanpa gejala klinis :

ü  Infus D10 diteruskan

ü  Periksa kadar glukosa tiap 3 jam

ü  ASI diberikan bila bayi dapat minum

§  Bila kadar glukosa ≥ 45 mg/dl dalam 2 kali pemeriksaan

ü  Ikuti petunjuk bila kadar glukosa sudah normal

ü  ASI diberikan bila bayi dapat minum dan jumlah infus diturunkan pelan-pelan

ü  Jangan menghentikan infus secara tiba-tiba

§  Kadar  glukosa darah < 45 mg/dl tanpa GEJALA

ü  ASI teruskan

ü  Pantau, bila ada gejala manajemen seperti diatas

ü  Periksa kadar glukosa tiap 3 jam atau sebelum minum, bila :

§  Kadar < 25 mg/dl, dengan atau tanpa gejala tangani hipoglikemi

§  Kadar 25-45 mg/dl naikkan frekwensi minum

§  Kadar ≥ 45 mg/dl manajemen sebagai kadar glukosa normal

§  Kadar glukosa normal IV teruskan

ü  IV teruskan

ü  Periksa kadar glukosa tiap 12 jam

Bila kadar glukosa turun, atasi seperti diatas

§  Bila bayi sudah tidak mendapat IV, periksa kadar glukosa tiap 12 jam, bila 2 kali pemeriksaan dalam batas normal, pengukuran dihentikan.

§  Persisten hipoglikemia (hipoglikemia lebih dari 7 hari)

ü  konsultasi endokrin

ü  terapi : kortikosteroid  hidrokortison 5 mg/kg/hari 2 x/hari iv atau prednison 2 mg/kg/hari per oral, mencari kausa hipoglikemia lebih dalam.

ü  bila masih hipoglikemia dapat ditambahkan obat lain : somatostatin, glukagon, diazoxide, human growth hormon, pembedahan. (jarang dilakukan)

Daftar Pustaka

§  Wilker RE. Hypoglycemia and hyperglycemia Dalam: Cloherty JP, Stark AR, eds. Manual of neonatal care; edisi ke-5. Boston : Lippincott Williams & Wilkins, 2004; 569-76

§  Raghuveer TS, Garg U, Graf WD. Inborn errors of metabolism in infancy and early childhood: an update. Am Fam Physician. Jun 1 2006;73(11):1981-90.

§  http://growupclinic.com/2012/08/10/penanganan-terkini-hipoglikemia-pada-bayi/. Access on 30^th August 2014, 16.00 WIB

NEONATAL HYPOGLYCEMIA

Neonatal hypoglycemia, defined as a plasma glucose level of less than 30 mg/dL (1.65 mmol/L) in the first 24 hours of life and less than 45 mg/dL (2.5 mmol/L) thereafter, is the most common metabolic problem in newborns. Major long-term sequelae include neurologic damage resulting in mental retardation, recurrent seizure activity, developmental delay, and personality disorders. Some evidence suggests that severe hypoglycemia may impair cardiovascular function.

Signs and symptoms

Infants in the first or second day of life may be asymptomatic or may have life-threatening central nervous system (CNS) and cardiopulmonary disturbances. Symptoms can include the following:

·         Hypotonia

·         Lethargy, apathy

·         Poor feeding

·         Jitteriness, seizures

·         Congestive heart failure

·         Cyanosis

·         Apnea

·         Hypothermia

Clinical manifestations associated with activation of the autonomic nervous system include the following:

·         Anxiety, tremulousness

·         Diaphoresis

·         Tachycardia

·         Pallor

·         Hunger, nausea, and vomiting

Clinical manifestations of hypoglycorrhachia or neuroglycopenia include the following:

·         Headache

·         Mental confusion, staring, behavioral changes, difficulty concentrating

·         Visual disturbances (eg, decreased acuity, diplopia)

·         Dysarthria

·         Seizures

·         Ataxia, somnolence, coma

·         Stroke (hemiplegia, aphasia), paresthesias, dizziness, amnesia, decerebrate or decorticate posturing

Diagnosis

Laboratory studies

·         Serum or plasma glucose levels

·         Serum insulin

·         Urine: Obtain a first-voided urine dipstick for ketones; send urine for organic acid analysis

·         Screening for metabolic errors: Electrospray ionization-tandem mass spectrometry in asymptomatic persons allows earlier identification of clearly defined inborn errors of metabolism, including aminoacidemias, urea cycle disorders, organic acidurias, and fatty acid oxidation disorders

Angiography

The detection of adenomas by celiac angiography has had limited success. The chance of detecting a tumor blush must be balanced against the potential risk of causing vascular trauma in infants younger than 2 years.

Management

Hypoglycemia should be treated as soon as possible to prevent complications of neurologic damage. Early feeding of the newborn with breast milk or formula is encouraged. The mainstay of therapy for children who are alert with intact airway protection includes orange juice at 20 mL/kg.

For patients who cannot protect their airway or are unable to drink, nasogastric, intramuscular, intraosseous, or intravenous (IV) routes can be employed for the following drugs used to raise glucose levels: dextrose, glucagon, diazoxide, and octreotide. Start a 5% or 10% dextrose drip when hypoglycemia is recurrent.

Surgery

Surgical exploration usually is undertaken in severely affected neonates who are unresponsive to glucose and somatostatin therapy. Near-total resection of 85-90% of the pancreas is recommended for presumed congenital hyperinsulinism, which is most commonly associated with an abnormality of beta-cell regulation throughout the pancreas. Risks include the development of diabetes.

Background

Hypoglycemia is the most common metabolic problem in neonates. In children, a blood glucose value of less than 40 mg/dL (2.2 mmol/L) represents hypoglycemia. A plasma glucose level of less than 30 mg/dL (1.65 mmol/L) in the first 24 hours of life and less than 45 mg/dL (2.5 mmol/L) thereafter constitutes hypoglycemia in the newborn.

Patients with hypoglycemia may be asymptomatic or may present with severe central nervous system (CNS) and cardiopulmonary disturbances. The most common clinical manifestations can include altered level of consciousness, seizure, vomiting, unresponsiveness, and lethargy. Any acutely ill child should be evaluated for hypoglycemia, especially when history reveals diminished oral intake. (See History and Physical Examination.)

Sustained or repetitive hypoglycemia in infants and children has a major impact on normal brain development and function. Evidence suggests that hypoxemia and ischemia potentiate hypoglycemia, causing brain damage that may permanently impair neurologic development. (See Prognosis.)

Causes of hypoglycemia in neonates differ slightly from those in older infants and children. The causes in neonates include the following (see Etiology):

·         Inappropriate changes in hormone secretion

·         Inadequate substrate reserve in the form of hepatic glycogen

·         Inadequate muscle stores as a source of amino acids for gluconeogenesis

·         Inadequate lipid stores for the release of fatty acids

Hyperinsulinism, or persistent hyperinsulinemic hypoglycemia of infancy (PHHI), is the most common cause of hypoglycemia in the first 3 months of life. It is well recognized in infants of mothers with diabetes. (See Etiology.)

Causes of hypoglycemia found in all ages include gram-negative sepsis, endotoxin shock, and ingestions, including of salicylates, alcohol, hypoglycemic agents, or beta-adrenergic blocking agents.

Excluding insulin therapy, almost all hypoglycemia in childhood occurs during fasting. Postprandial hypoglycemia is rare in children in the absence of prior gastrointestinal (GI) surgery. Management efforts are directed toward the immediate normalization of glucose levels and the identification and treatment of the various causes.

Patient education

Provide genetic counseling for families with affected children, including information about a possible 25% risk of recurrence. Educate pregnant women with diabetes.

Glucose metabolism

Normal blood glucose is very narrowly regulated, usually from 80-90 mg/dL (4.4-5 mmol/L). Glucose levels increase transiently after meals to 120-140 mg/dL (6.6-7.7 mmol/L). Feedback systems return the glucose concentration rapidly back to the preprandial level, usually within 2 hours after the last absorption of carbohydrates.

Insulin and glucagon are the important hormones in the immediate feedback control system of glucose. When blood glucose increases after a meal, the rate of insulin secretion increases and stimulates the liver to store glucose as glycogen. When cells (primarily liver and muscle) are saturated with glycogen, additional glucose is stored as fat.

When blood glucose levels fall, glucagon secretion functions to increase blood glucose levels by stimulating the liver to undergo glycogenolysis and release glucose back into the blood. (See the diagram below.)

Normal hypoglycemic counterregulation.

In starvation, the liver maintains the glucose level via gluconeogenesis. Gluconeogenesis is the formation of glucose from amino acids and the glycerol portion of fat. Muscle provides a store of glycogen and muscle protein breaks down to amino acids, which are substrates utilized in gluconeogenesis in the liver. Circulating fatty acids are catabolized to ketones, acetoacetate, and B-hydroxybutyrate and can be used as auxiliary fuel by most tissues, including the brain.

The hypothalamus stimulates the sympathetic nervous system, and epinephrine is secreted by the adrenals, causing the further release of glucose from the liver. Over a period of hours to days of prolonged hypoglycemia, growth hormone and cortisol are secreted and decrease the rate of glucose utilization by most cells of the body.

In the newborn, serum glucose levels decline after birth until age 1-3 hours, then they spontaneously increase. Liver glycogen stores become rapidly depleted within hours of birth, and gluconeogenesis, primarily from alanine, can account for 10% of glucose turnover in the newborn infant by several hours of age.

Etiologi

The causes of neonatal hypoglycemia include the following:

·         PHHI

·         Limited glycogen stores (eg, prematurity, intrauterine growth retardation)

·         Increased glucose use (eg, hyperthermia, polycythemia, sepsis, growth hormone deficiency)

·         Decreased glycogenolysis, gluconeogenesis, or use of alternate fuels (eg, inborn errors of metabolism, adrenal insufficiency)

·         Depleted glycogen stores (eg, asphyxia-perinatal stress, starvation)

With regard to the last item above, in ketotic hypoglycemia, easily depleted glycogen stores, in combination with inadequate production of glucose through gluconeogenesis, contribute to hypoglycemia. Thus, fatty acid oxygenation is required to provide substrate for gluconeogenesis and ketogenesis. Ketones, the byproduct of fatty acid metabolism, are found in urine and represent the starved state.

Causes of hypoglycemia in older infants, children, and teenagers include:

·         Poisonings/drugs (eg, ethanol, isoniazid, insulin, propranolol, salicylates, oral hypoglycemics, pentamidine, quinine, disopyramide, unripe ackee fruit, Vacor [rat poison]).

·         Liver disease (eg, Reye syndrome, hepatitis, cirrhosis, hepatoma)

·         Amino acid and organic acid disorders (eg, maple syrup urine disease,propionic acidemia, methylmalonic acidemia, tyrosinosis, glutaric aciduria, 3-hydroxy-3-methylglutaric aciduria)

·         Systemic disease (eg, sepsis, burns, cardiogenic shock, respiratory distress syndrome)

Hyperinsulinemia

Congenital hyperinsulinism is most commonly associated with an abnormality of beta-cell regulation throughout the pancreas. A focal disease, such as isolated islet adenoma, occasionally causes congenital hyperinsulinism.

Genetic defects have been delineated and now replace the older terms, such as nesidioblastosis, leucine-sensitive hypoglycemia, PHHI, and islet dysregulation syndrome. These defects are in the sulfonylurea receptor (SUR) and the beta-cell potassium adenosine triphosphate (ATP) channel gene located on the short arm of chromosome 11.

Drug-induced hyperinsulinism is secondary to surreptitious insulin administration or the use of oral hypoglycemic drugs. Exogenous administration of insulin is diagnosed with low serum levels of C-peptide. The sulfonylureas are commonly prescribed for adults; thus, they are available to children as unintentional ingestions. In these cases, hypoglycemia may persist for more than 24 hours. Diazoxide administration may be helpful by suppressing insulin secretion in severe cases.

Epidemiology

Occurrence in the United States

The overall incidence of symptomatic hypoglycemia in newborns varies from 1.3-3 per 1000 live births. Incidence varies with the definition, population, method and timing of feeding, and the type of glucose assay. Serum glucose levels are higher than whole blood values. The incidence of hypoglycemia is greater in high-risk neonatal groups.

Early feeding decreases the incidence of hypoglycemia. Inborn errors of metabolism that lead to neonatal hypoglycemia are rare but can be screened in infancy. The incidences of these conditions are as follows:

·         Carbohydrate metabolism disorders (>1:10,000)

·         Fatty acid oxidation disorders (1:10,000)

·         Hereditary fructose intolerance (1:20,000 to 1:50,000)

·         Glycogen storage diseases (1:25,000)

·         Galactosemia (1:40,000)

·         Organic acidemias (1:50,000)

·         Phosphoenolpyruvate carboxykinase deficiency (rare)

·         Primary lactic acidosis (rare)

International occurrence

In a Japanese study, more than 80% of admissions from the nursery to the neonatal intensive care unit (ICU) after birth were due to apnea or hypoglycemia in neonates born at 35-36 weeks' gestation.

History

The clinical presentation of hypoglycemia reflects decreased availability of glucose for the CNS as well as adrenergic stimulation caused by a decreasing or low blood sugar level. During the first or second day of life, symptoms vary from asymptomatic to CNS and cardiopulmonary disturbances.

High-risk groups who need screening for hypoglycemia in the first hour of life include the following:

·         Newborns who weigh more than 4 kg or less than 2 kg

·         Large for gestational age (LGA) infants who are above the 90th percentile, small for gestational age (SGA) infants below the 10th percentile,^[5] and infants with intrauterine growth restriction

·         Infants born to insulin-dependent mothers (1:1000 pregnant women) or mothers with gestational diabetes (occurs in 2% of pregnant women)

·         Gestational age less than 37 weeks

·         Newborns suspected of sepsis or born to a mother suspected of having chorioamnionitis

·         Newborns with symptoms suggestive of hypoglycemia, including jitteriness, tachypnea, hypotonia, poor feeding, apnea, temperature instability, seizures, and lethargy

Additionally, consider hypoglycemia screening in infants with significant hypoxia, perinatal distress, 5-minute Apgar scores of less than 5, isolated hepatomegaly (possible glycogen-storage disease), microcephaly, anterior midline defects, gigantism, macroglossia or hemihypertrophy (possible Beckwith-Wiedemann Syndrome), or any possibility of an inborn error of metabolism or whose mother is on terbutaline, beta blockers, or oral hypoglycemic agents

The onset of hyperinsulinemia is from birth to age 18 months. Insulin concentrations are inappropriately elevated at the time of documented hypoglycemia. Transient neonatal hyperinsulinism occurs in macrosomic infants of diabetic mothers (who have diminished glucagon secretion and in whom endogenous glucose production is significantly inhibited). Clinically, these infants are macrosomic and have increasing demands for feeding, intermittent lethargy, jitteriness, and frank seizures.

Infants with prolonged neonatal hyperinsulinism can be described by the following:

·         SGA

·         Having perinatal asphyxia

·         Born to mothers with toxemia

·         Having high rates of glucose use and often requiring dextrose infusion for a prolonged period of time

Ketotic hypoglycemia is an uncommon, but dramatic, illness. It is observed in children younger than age 5 years, who usually become symptomatic after an overnight or prolonged fast, especially with illness and poor oral intake. Children often present as inexplicably lethargic or frankly comatose, having only marked hypoglycemia with ketonuria.

Physical Examination

Clinical manifestations are broad and can result from adrenergic stimulation or from decreased availability of glucose for the CNS. Unlike older children, infants are not able to verbalize their symptoms and are particularly vulnerable to hypoglycemia.

Infants in the first or second day of life may be asymptomatic or have life-threatening CNS and cardiopulmonary disturbances. Symptoms can include the following:

·         Hypotonia

·         Lethargy, apathy

·         Poor feeding

·         Jitteriness, seizures

·         Congestive heart failure

·         Cyanosis

·         Apnea

·         Hypothermia

Clinical manifestations associated with activation of the autonomic nervous system include the following:

·         Anxiety, tremulousness

·         Diaphoresis

·         Tachycardia

·         Pallor

·         Hunger, nausea, and vomiting

Clinical manifestations of hypoglycorrhachia or neuroglycopenia include the following:

·         Headache

·         Mental confusion, staring, behavioral changes, difficulty concentrating

·         Visual disturbances (eg, decreased acuity, diplopia)

·         Dysarthria

·         Seizures

·         Ataxia, somnolence, coma

·         Stroke (hemiplegia, aphasia), paresthesias, dizziness, amnesia, decerebrate or decorticate posturing

Diagnostic Considerations

Consider the diagnosis of hypoglycemia, especially in a patient with sustained or repetitive episodes of hypoglycemia with resulting seizures and mental retardation. Conditions to consider in the differential diagnosis of hypoglycemia include the following:

·         Fasting

·         Malnutrition

·         Diarrhea

·         Enzymatic defects of glycogen synthetic pathways

·         Enzymatic defects of glycogenolytic pathways

·         Enzymatic defects of gluconeogenic pathways

·         Glucagon deficiency

·         Congenital hyperinsulinism (eg,nesidioblastosis, leucine sensitive hypoglycemia)

·         Defects of beta cell regulation

·         Large tumors

·         Decreased or absent fat stores

·         Enzymatic defects in fatty acid oxidation

Differential Diagnoses

·         Adrenal Insufficiency and Adrenal Crisis

·         Hypopituitarism

·         Hypothyroidism and Myxedema Coma

·         Munchausen Syndrome

·         Pediatrics, Reye Syndrome

·         Plant Poisoning, Hypoglycemics

·         Shock, Septic

·         Toxicity, Alcohols

·         Toxicity, Salicylate

Workup

Approach Considerations

Fingerstick glucose levels or bedside testing may lead to overtreatment of hypoglycemia, because the primary error with the chemically treated strips is an underestimation of the serum glucose value.

Serum or plasma glucose levels

Serum glucose level is higher than whole blood glucose level. Whole blood measurements of glucose may underestimate the plasma glucose concentration by approximately 10-15%, because red blood cells (RBCs) contain relatively low concentrations of glucose. Arterial and capillary samples may overestimate the plasma glucose concentration by 10% in nonfasting patients. Hold an extra tube of serum or plasma and refrigerate until laboratory glucose is known.

Serum insulin

When blood glucose is less than 40 mg/dL, plasma insulin concentration should be less than 5 and no higher than 10 µU/mL. This testing may not be available in the emergency department.

Urine

Obtain a first voided urine dipstick for ketones. Failure to find large ketones with hypoglycemia suggests that fat is not being metabolized from adipose tissue (hyperinsulinism) or that fat cannot be used for ketone body formation (enzymatic defects in fatty acid oxidation). Send urine for organic acid analysis.

Screening for metabolic errors

Electrospray ionization-tandem mass spectrometry in asymptomatic persons allows earlier identification of clearly defined inborn errors of metabolism. These disorders include aminoacidemias, urea cycle disorders, organic acidurias, and fatty acid oxidation disorders. Earlier recognition of these inborn errors of metabolism has the potential to reduce morbidity and mortality rates in infants with these conditions. This testing may not be available in the emergency department.

Imaging studies

The detection of adenomas by celiac angiography has had limited success. The chance of detecting a tumor blush must be balanced against the potential risk of causing vascular trauma in infants younger than age 2 years. This testing may not be available in the emergency department.

Treatment

Approach Considerations

Start a 5% or 10% dextrose drip when hypoglycemia is recurrent. In terms of prehospital care, stabilize acute, life-threatening conditions and initiate supportive therapy in patients with hypoglycemia. If a patient is alert and has intact airway protective reflexes, oral liquids containing sugar (eg, orange juice) can be administered.

Emergency department care

Supportive therapy includes oxygen, establishing an intravenous (IV) line, and monitoring. Seizures unresponsive to correction of hypoglycemia should be managed with appropriate anticonvulsants. Marked acidosis (pH < 7.1) suggests shock or serious underlying disease and should be treated appropriately. The treatment goal is to maintain a blood glucose level of at least 45 mg/dL (2.5 mmol/L).

For the infant or child who does not drink but has intact airway protective reflexes, orogastric or nasogastric administration of oral liquids containing sugar may be performed.

Inpatient care

Any child with documented hypoglycemia not secondary to insulin therapy should be hospitalized for careful monitoring and diagnostic testing.

Surgery

If hypoglycemia is diagnosed in an infant younger than 3 months, surgical intervention may be necessary. Surgical exploration usually is undertaken in severely affected neonates who are unresponsive to glucose and somatostatin therapy. Near-total resection of 85-90% of the pancreas is recommended for presumed congenital hyperinsulinism, which is most commonly associated with an abnormality of beta-cell regulation throughout the pancreas. Risks include the development of diabetes.

Medication

Hypoglycemia should be treated as soon as possible to prevent complications of neurologic damage. Early feeding of the newborn with breast milk or formula is encouraged. For those unable to drink, a nasogastric tube can be used. The mainstay of therapy for children that are alert with intact airway protection includes orange juice at 20 mL/kg.

For those who cannot protect their airway or are unable to drink, nasogastric, intramuscular, intraosseous, or IV routes can be employed for the following drugs used to raise glucose levels: dextrose, glucagon, diazoxide, and octreotide. Case reports have shown that nifedipine may help to maintain normoglycemia in children with PHHI.

Cortisol should not be used, because it has minimal acute benefit and may delay the diagnosis of the cause of hypoglycemia. Cortisol stimulates gluconeogenesis and causes decreased use of glucose, which leads to overall elevated blood glucose and may mask the true cause of hypoglycemia.

Anti-hypoglycemic Agents

These agents elevate blood glucose levels.

Dextrose

Dextrose is the treatment of choice. It is absorbed from the intestine, resulting in a rapid increase in blood glucose concentration when administered orally. Give IV dextrose to infants of diabetic mothers with transient neonatal hyperinsulinemia for several days until hyperinsulinemia abates. Avoid hyperglycemia evoking prompt insulin release, which may produce rebound hypoglycemia. SGA infants and those with maternal toxemia or perinatal asphyxia require dextrose IV infusion rates of more than 20 mg/kg/minute to control levels. Treatment may be necessary for 2-4 weeks.

Hypoglycemia

PO: As adults; 10-20 g as a single dose

IV: 0.5-1 g/kg up to 25 g 

Dilute before IV administration, may give more concentrated solution peripherally in emergency (ie, 12.5-25%)

Diazoxide (Proglycem)

Diazoxide increases blood glucose by inhibiting pancreatic insulin release and possibly through an extrapancreatic effect. A hyperglycemic effect starts within an hour and usually lasts a maximum of 8 hours with normal renal function. Diazoxide is reportedly effective in SGA infants and in those with maternal toxemia or perinatal asphyxia.

Dosing Forms & Strengths

oral suspension

50mg/mL

Hypoglycemia

Indicated for hypoglycemia due to hyperinsulinism associated with leucine sensitivity, islet cell hyperplasia, nesidioblastosis, extrapancreatic malignancy, islet cell adenoma, or adenomatosis

Newborn/infant: 10 mg/kg/day PO divided q8hr initially; typical dosage range is 8-15 mg/kg/day PO divided q8-12hr

Children: 3 mg/kg/day PO divided q8hr initially; typical dose range is 3-8 mg/kg/day PO divided q8-12hr  

Octreotide (Sandostatin) 

Octreotide is a long-acting analog of somatostatin that suppresses insulin secretion for the short-term management of hypoglycemia.

Dosing Forms & Strengths

injectable solution

·         0.05mg/mL

·         0.1mg/mL

·         0.2mg/mL

·         0.5mg/mL

·         1mg/mL

depot injection

·         10mg/kit

·         20mg/kit

·         30mg/kit

Acromegaly

Solution: 50 mcg SC q8hr initially; titrate up to 500 mcg SC q8hr if necessary; after successful treatment with solution for 2 weeks, initiate treatment with suspension (depot injection)

Suspension (depot injection): 20 mg IM (gluteal) every 4 weeks for 3 months; titrate up or down to 10-30 mg IM every 4 weeks, depending on response; not to exceed 40 mg, as follows

Symptoms controlled: If GH < 1 ng/mL and IGF-1 normal, decrease dose to 10 mg IM every 4 weeks; if GH < 2.5 ng/mL and IGF-1 normal, maintain dose at 20 mg IM every 4 weeks

Symptoms uncontrolled: If GH > 2.5 ng/mL or IGF-I elevated, increase dose to 30 mg IM every 4 weeks; if symptoms persist, increase to 40 mg IM

Dosing Considerations

·         Monitor IGF-1 levels every 2 weeks to guide titration; goal: GH levels <5 ng/mL or IGF-1 levels <1.9 units/mL (men) and <2.2 units/mL (women)

·         Monitor IGF-1 or GH levels every 6 months

·         Withdraw drug yearly for 4 weeks (solution) or 8 weeks (suspension) from patients who have undergone irradiation to assess

Glucagon (Glucagon Emergency Kit, GlucaGen) 

Glucagon may be used to treat hypoglycemia secondary to hyperinsulinemia and can be administered to patients without initial IV access. Each mL contains 1 mg (ie, 1 U). Maximal glucose concentration occurs between 5-20 minutes after IV administration and about 30 minutes after intramuscular (IM) administration.

Dosing Forms & Strengths

injection, powder

1mg/vial

Hypoglycemia

Indicated for severe hypoglycemic reactions in patients with diabetes treated with insulin

Administer oral glucose/IVdextrose to replete glycogen stores

GlucaGen

·         <25 kg or <6-8 years old and weight unknown: 0.5 mL SC/IM/IV

·         >25 kg or older than 6-8 years and weight unknown: 1 mL SC/IM/IV

Glucagon Emergency Kit

·         <20 kg: 0.5 mg SC/IM/IV q20min PRN, OR 0.2-0.3 mg/kg SC/IM/IV q20min PRN

·         >20 kg or older than 6-8 years: 1 mg SC/IM/IV q20min PRN

Prognosis

Hypoglycemia is the most common metabolic problem in neonates. Still, the level or duration of hypoglycemia that is harmful to an infant's developing brain is not known. Major long-term sequelae include neurologic damage resulting in mental retardation, recurrent seizure activity, developmental delay, and personality disorders. Some evidence suggests that severe hypoglycemia may impair cardiovascular function.

Remission of congenital hyperinsulinism generally does not occur, but the severity of the disease may decrease with time.

Sumber: http://emedicine.medscape.com/article/802334-workup Hilarie Cranmer, MD, MPH, FACEP  Director of Disaster Response, MGH Center for Global Health; Attending Physician, Department of Emergency Medicine, Massachusetts General Hospital; Assistant Professor, Harvard Medical School and School of Public Health