When Do Day-Night Circadian Rhythms Really Start for Infants?

Patient Presentation
A 4-day-old male came to clinic for his first well child check after discharge. Although he would awake to feed every 2-2.5 hours, his mother said that he would not latch well and would come off the breast often. She felt that when he did latch well, he would rhythmically suck and she could see his ear moving and see milk in his mouth afterwards. He was urinating 4-5 times/day and was stooling small amounts 5 or more times/day. His mother appeared somewhat disheveled and easily broke into tears saying that “I haven’t slept at all.” The father said that he was trying to help but the mother was very concerned about the feeding and wasn’t sleeping much. The past medical history showed a full term male with uneventful pregnancy or delivery who was discharged on day 2 of life. The family history was non-contributory.

The pertinent physical exam showed a somewhat sleepy infant who would awaken and root. His weight was 3258 grams which was 8% decreased from his birthweight and 2% decreased from his discharge weight. He was mildly jaundiced to the abdomen but the rest of his examination was normal. The work-up of a transcutaneous bilirubin showed a level of 10.2 mg/dL.

The diagnosis of a term male was made and breastfeeding support to help with the infant’s latch was given to the mother by a lactation nurse in the clinic. The pediatrician emphasized that both parents needed to rest and try to sleep when the baby slept. Other family members were available close by to also support the family. “It’s going to be a while before he knows day from night, so you are going to need to sleep or rest as much as you can when he does and leave some of the household chores to other people. Let them take care of you,” he advised. The patient’s clinical course at his next appointment in 2 days showed that the infant’s weight had increased by 30 grams. He was latching better although not perfectly and appeared more contented after eating. He was less jaundiced also. The mother also looked better and said that she had been trying to sleep as she could. They also gave the baby a bottle once at night so that she could sleep for about 4 hours. “It’s going a little better but he still has his days and nights mixed up,” she said.

Discussion
The earth rotates on its axis approximately every 24 hours with corresponding changes in ambient light occurring over that time period. Circadian systems have evolved in almost all living organisms to adapt to the changes in environmental light conditions and include sleep-wake cycles and changes in daily hormone production. In mammals , “[c]ircadian clocks resident in nearly every, if not all, mammalian cells…” and have been detected in embryonic stem cells. The circadian timing system has 3 major components – a central biological clock, input pathways and output pathways.

The central biological clock in the suprachiasmatic nuclei (SCN) isin the anterior hypothalamus just above the optic chiasm. There are peripheral biological clocks such as the liver also but they play less importance. The SCN oscillations (or rhythmic changes) are about 24 hours in length, but not exactly and stimulation is needed daily to reset the SCN and prevent it from drifting or freely running out of phase.

Input pathways are mainly from light which strikes the retina sending messages directly to the SCN or from the retina to the retinohypothalmic tract and then to the SCN. Output pathways are to the hypothalamus and other nonhypothalamic sites that regulate the daily changes of several hormones including melatonin and cortisol, which are two of the most important hormonal circadian regulators. Melatonin is produced in the pineal gland. Melatonin is the main hormone that regulates the daily resetting of the SCN and appears to be a main hormone for circadian rhythm entrainment for neonates and infants.

Primate studies have found that the SCN develops during gestational days 27-48, and metabolic activity is present by the end of gestation. The main SCN day-night settings appear to be set by the end of gestation but need to be entrained after birth. Entrainment appears to be mainly regulated by light cycles in neonates but feeding activities and temperature also appear to play a part of the entrainment. Other maternal time-of-day cues may also play a part.

Learning Point
For term human neonates there are few day-night rhythms detected. Infant activities are evenly distributed over the 24 hour cycle. However by 1-2 months of age, awake activities are consolidating more during daytime hours and by 3 months of age daytime sleeping decreases further with more sleep occurring at night. Day-night melatonin production is detectable by 12 weeks of age and by 3-6 months circadian cortisol variations are seen.

Questions for Further Discussion
1. What are some of the health problems related to inadequate sleep? To review click here.
2. How do circadian rhythms differ for preterm infants relative to full term infants?
3. Does taking melatonin help with jet lag?
4. What are SIDS prevention techniques?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Sleep Disorders

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Rivkees SA. Emergence and influences of circadian rhythmicity in infants. Clin Perinatol. 2004 Jun;31(2):217-28, v-vi.

Feldman R. The development of regulatory functions from birth to 5 years: insights from premature infants. Child Dev. 2009 Mar-Apr;80(2):544-61.

Christ E, Korf HW, von Gall C. When does it start ticking? Ontogenetic development of the mammalian circadian system. Prog Brain Res. 2012;199:105-18.

Sumova A, Sladek M, Polidarova L, Novakova M, Houdek P. Circadian system from conception till adulthood. Prog Brain Res. 2012;199:83-103.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

Intussusception By The Numbers

Patient Presentation
A pediatrician heard from a colleague about a 4-year-old male with intussusception who was successfully reduced by air enema but recurred 8 hours later. The child again was successfully reduced but recurred several days later. The colleague noted that the evaluation for a potential anatomic pathological lead point was negative and fortunately the child had not recurred again. The pediatrician started thinking about the rates of recurrence, radiological reduction success, and the causes of pathological lead points.

Discussion
Intussusception occurs when one segment of the gastrointestinal tract telescopes into an adjacent segment. The outer receiving segment of bowel is known as the intussuscipiens and the inner inverting segment is known as the intussusceptum. It occurs most often in children between 2 months to 5 years, with a peak incidence between 4-10 months. Males are more often affected than females by 3:2. It also occurs more often after abdominal operations particularly in the first 2 weeks. It is the second most common acute abdominal emergency in children after appendicitis. In adults ~80% have an underlying cause or lead point such as a polyp, tumor, fibrosis, endometriosis, etc.. The cause is usually idiopathic in children (95%) but it is hypothesized that in children it is caused by a viral induced edema of the Peyer’s patches in the ileum that serves as a lead point, but this hypothesis has not been confirmed. It commonly occurs near the ileocecal valve.

A review of intussusception presentations can be found here.

Learning Point
The numbers are positive for intussusception patients. There is a high rate of spontaneous reduction and even better rates for radiological reduction. Recurrence rates are relatively low and pathological causes are even lower.

Intussusception numbers

  • Natural history
    • Spontaneous reduction = 17% or higher
    • Perforation risk = 0-6% with most series being <1% for spontaneous perforation
  • Radiological reduction
    • Successful reduction can be as high as 99% with barium enema and 92% with air enema depending on patient characteristics
  • Recurrence
    • Recurrence rate = ~20% overall that occur at any age, age at first episode of intussusception is not predictive of recurrence risk
      • Recurrence risk in first 24 hours is 2.2 – 3.9% and in first 48 hours is 2.7 – 6.6%
    • Pathological lead points are 1.5-12% of intussusceptions, they are more common in older ages (5-14 years)

Potential causes of pathological lead points in intussusception include:

  • Meckel’s diverticulum **
  • Polyps **
    • Single, idiopathic
    • Familial polyposis
    • Peutz-Jeghers syndrome
  • Gastrointestinal duplication**
  • Vascular
    • Henoch-Schonlein purpura
    • Hemangioma
    • Intramural hematoma
    • Lymphangectasia
  • Appendix
    • Appendicitis or periappendicitis
    • Appendix invagination
  • Ectopic tissues
    • Gastric mucosa
    • Pancreas
  • Infectious diseases
    • Adenovirus
    • Calcivirus
    • Echovirus
    • Escherichia coli
    • Rotavirus
    • Tuberculosis
  • Suture line or stricture
  • Tumors
    • Adenocytoma
    • Hamartoma
    • Kaposi sarcoma
    • Lymphoma **
  • Other
    • Catheters
    • Celiac disease
    • Colitis
      • Hirschsprung
      • Neutropenic
    • Cystic Fibrosis
    • Massive lymphoid hyperplasia

** = most common causes of pathological lead point
Questions for Further Discussion
1. Using ultrasound, what is the radiological sign for intussusception called?
2. Describe how the barium or air enema is done for intussusception.

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Intestinal Obstruction and Abdominal Pain.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Navarro O, Daneman A. Intussusception. Part 3: Diagnosis and management of those with an identifiable or predisposing cause and those that reduce spontaneously. Pediatr Radiol. 2004 Apr;34(4):305-12.

Maazoun K, Mekki M, Sahnoun L, Hafsa S, Ben Brahim M, Belghith M, Zakhama A, Jouini R, Golli M, Krichene I, Nouri A. Intussusception owing to pathologic lead points in children: report of 27 cases. Arch Pediatr. 2007 Jan;14(1):4-9.

Justice FA, Nguyen LT, Tran SN, Kirkwood CD, Thi NT, Carlin JB, Bines JE. Recurrent intussusception in infants. J Paediatr Child Health. 2011 Nov;47(11):802-5.

Gray MP, Li SH, Hoffmann RG, Gorelick MH. Recurrence rates after intussusception enema reduction: a meta-analysis. Pediatrics. 2014 Jul;134(1):110-9.

Rubinstein JC, Liu L, Caty MG, Christison-Lagay ER. Pathologic leadpoint is uncommon in ileo-colic intussusception regardless of age. J Pediatr Surg. 2015 Mar 26.

Author
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

At What Level Does Elevated Glucose Cause Glucosuria?

Patient Presentation
A 6-year-old female came to clinic with a history of frequent urination. She was toilet trained around 3 years of age during the day, and around 4 years of age at night. Her mother said that she had occasional daytime urinary accidents but over the last week she was having them 2-4 times/day during the day only. The girl denied any dysuria, abdominal pain, voiding small amounts, having problems passing urine or changes in urine color. Her mother was not sure if she was having any dribbling. The patient initially denied but later stated that she was not stooling very often. The past medical history was negative except for one uncomplicated urinary tract infection when she was 4 years old. The family history was negative for kidney disease or diabetes. The review of systems was negative for excessive thirst, polydipsia, or nocturnal enuresis. The family denied any weight loss or changes in how her clothes were fitting.

The pertinent physical exam showed a well-appearing female with normal vital signs. Her growth parameters were in the 75-90% and she had gained weight since her last visit 5 months ago. HEENT was negative including an appropriately sized thyroid gland. Her abdominal examination had palpable stool in the left lower quadrant. Her genitourinary examination was negative. Her back had no skin or spinal defects noted and she had a normal neurological examination.

The resident physician’s differential diagnosis included the diagnosis of constipation causing diurnal enuresis, a urinary tract infection and diabetes. When the attending physician asked why she was concerned about diabetes she said that the inpatient team had recently admitted a younger child who had type 1 diabetes and diabetic ketoacidosis who presented with enuresis. When pressed what else in the history and physical examination lead her to think about diabetes she replied, “I know that this is not that common, but I just worry.” The attending noted that it was always good to be concerned but this child had no other symptoms such as polydipsia, weight changes, other illnesses. “It’s also less likely because the child does not have nocturnal enuresis. Although patients can have intermittent glucosuria causing enuresis, its more likely that they would have enuresis at night too,” the attending noted. The attending then went on, “We’ll get the urinalysis because she has had an UTI in the past plus it will tell us if there is glucosuria. I don’t remember exactly how high the blood glucose has to be before it spills into the urine but it’s fairly high I think.” The laboratory testing of a urinalysis was normal with no ketones, glucose, leukocyte esterase or nitrates. The patient’s clinical course was that she was sent home with instructions for constipation management with followup in 1 month.

Discussion
Constipation generally is defined as infrequent or painful defecation. Most children develop constipation after the child begins to associate pain (e.g. a hard bowel movement) with defecation. The child then begins to withhold the stools trying to decrease the defecation discomfort. As stool withholding continues, the rectum dilates and gradually accommodates with the normal defecation urge disappearing. Passing large hard stools infrequently reinforces the defecation pain. The cycle continues. If the cycling is severe enough, worsening stool retention and more abnormal defecation dynamics occurs. Chronic rectal distension results in both loss of rectal sensitivity, and loss of urge to defecate, which can lead to encopresis. The differential diagnosis of constipation can be reviewed here.

Constipation can also lead to enuresis because of increased pressure on the bladder and also because of inappropriate toileting behaviors where children infrequently voids as well as defecates. The differential diagnosis of diurnal enuresis can be reviewed here.

Type 1 diabetes mellitis is one of the most common chronic diseases in childhood and is increasing in prevalence worldwide. In childhood the presentation age is bimodal with one peak at 4-6 years and another at 10-14 years. Most studies show no gender differences except for an increase in older adolescent males noted in European studies. The diagnosis is made by a fasting glucose of > 126 mg/dL (7 mmol), or postprandial glucose of > 200 mg/dL (11.1 mmol), or hemoglobin A1c > 6/5% (48 mmol/mol), in addition to insulin deficiency and clinical signs of insulin deficiency (such as those in the classic presentation below).

The presentations of type 1 diabetes includes:

  • Hyperglycemia without acidosis
    • Classic presentation – polyuria, polydipsia and weight loss
    • Polyuria and polydipsia are seen in the vast majority of cases (90%); weight loss occurs in about 1/2 of children. Nocturnal enuresis is a very common early symptom.
    • Symptoms usually have been occurring for 10 days
    • Symptoms can be subtle so a careful history is needed especially in young children where polyuria may be more difficult to identify. Young children may also present with dehydration, abdominal pain, fatigue or a prolonged candidal infection.
    • Patients may appear relatively well
  • Diabetic ketoacidosis
    • Less common presentation (~10%) of patients
    • Similar to classic presentation but patients usually appear more ill
    • May have fruity-smelling breath and mental status changes such as lethargy and drowsiness
  • Occult
    • Patient diagnosed because of family history or tested for other reasons
  • Non-specific symptoms
    • Abdominal pain
    • Emesis
    • Growth retardation
    • Infectious diseases including perineal candidiasis
    • Lethargy
    • Pruritis
    • School or mental problems
    • Visual changes
    • Weakness

Learning Point
The renal glomerulus filters glucose which is reabsorbed by the proximal convoluted tubule.
Polyuria occurs when the serum glucose concentration overwhelms the tubules ability to reabsorb the glucose.
This occurs at serum glucose concentrations above 180 mg/dL (10 mmol/L).

Questions for Further Discussion
1. How does Type 2 diabetes mellitis present?
2. What are risk factors for diabetes mellitus?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for these topics: Constipation, Diabetes and Diabetes Type 1.

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

Vanelli M, Scarabello C, Fainardi V. Available tools for primary ketoacidosis prevention at diabetes diagnosis in children and adolescents. “The Parma campaign”. Acta Biomed. 2008 Apr;79(1):73-8.

Schultz-Lampel D, Steuber C, Hoyer PF, Bachmann CJ, Marschall-Kehrel D, Bachmann H. Urinary incontinence in children. Dtsch Arztebl Int. 2011 Sep;108(37):613-20.

Merger SR, Leslie RD, Boehm BO. The broad clinical phenotype of Type 1 diabetes at presentation. Diabet Med. 2013 Feb;30(2):170-8.

Levitsky LL, Misra M. Epidemiology, Presentation, and Diagnosis of Type 1 Diabetes Mellitis in Children and Adolescents. UpToDate.
(rev. 6/10/14, cited 7/14/15).

Levitsky LL, Misra M. Complications and Screening in Children and Adolescents with Type 1 Diabetes Mellitis. UpToDate.
(rev. 1/2/2015, cited 7/14/15).

Author

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital

Should Ondansetron Be Used for Acute Gastroenteritis?

Patient Presentation
A 6-year-old female came to the clinic with emesis and diarrhea. She had been well but had onset of emesis 10 hours prior to coming to clinic and 2 episodes of loose water stools without blood. The emesis was of fluid and food without blood or a bilious color. The parent had tried some oral rehydration solution (ORS) but the patient had emesis of the fluid so the mother stopped giving it to her. She also started to have diarrhea about 4 hours previously with 2 loose, watery stools without blood. Her last urination was 6 hours ago. She had no obvious ill contacts. The past medical history showed a healthy patient and the review of systems was negative for fever, chills, or cough. The pertinent physical exam showed a tired appearing female with normal vital signs except for a weight that was down 680 grams from a weight 1 month ago. She had mildly dry lips but moist mucous membranes. Her capillary refill was approximately 2 seconds. Her examination was otherwise normal. The diagnosis of acute gastroenteritis with mild dehydration was made. The parent was instructed on how to give ORS and also given 1 dose of oral ondansetron. The patient had emesis once not long after starting the rehydration but then starting feeling somewhat better. By 2-3 hours later she had taken an additional 12 ounces without emesis and had urinated. The patient was sent home with instruction about how to continue to give the ORS, how to restart a regular diet and when to call the clinic.

Discussion
Acute gastroenteritis (AGE) is a common illness worldwide and is “…defined as a decrease in the consistency of stools (loose or liquid) and/or an increase in the frequency of evacuations with or without fever or vomiting….” It is one of the most common reasons for seeking medical care and hospitalizations. In Europe, rotavirus and noroviruses are two of the most frequent viral agents causing AGE and Campylobacter and Salmonella are the most common bacterial AGE causes. For parasitic infections Giardia, and Crytosporidium are most common parasitic infections in Europe.

Recommendations for AGE treatment include oral rehydration, nasogastric rehydration and or intravenous rehydration. The European Society of Pediatric Gastroentrology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases recommends oral and nasogastric rehydration before trying intranveous rehydration. They note that “…oral rehydration is more effective and less invasive than IV rehydration and the administration of [oral rehydration solutions] should be attempted and promoted.” Additionally if IV therapy is used, patients “… should be made to switch or oral rehydration as soon as indication for parental rehydration are no longer observed.” Those indications for IV rehydration include shock, dehydration that is accompanied by a change of consciousness or severe acidosis, worsening dehydration or lack of improvement despite oral or NG rehydration, persistent emesis despite oral or NG therapy or severe abdominal distention and ileus.

According to the European guidelines, in addition to rehydration, some absorbents (i.e. Diosmectite) and antisecretory medication (i.e. Racecadotril) can be considered for AGE, but some agents are not available in all countries. Probiotics (eg. L. rhamnosus GG and S. boulardii) should be considered for use with AGE as an adjunct to rehydration therapy according to these guidelines. Drug therapy that is not recommended includes the antimotiity agent loperamide, the antisecretory agent bismuth subsalicylate, symbiotics, prebiotics, folic acid and gelatine tannate. The guidelines also note that antiinfective therapy is generally not used in the “…vast majority of healthy children with acute gastroenteritis…” and “… is not needed routinely but only for specific pathogens or in defined clinical settings.”

AGE can cause visceral stimulation of the gut causing dopamine and serotonin to be released which in turn causes the medullary vomiting center to be stimulated which thereby causes nausea and emesis. Ondansetron (Zofran®) is a setotonin antagonist (5-HT3 receptor) used to treat this effect. The site of action is not entirely known and may be in the viscera, the medulla or both. A recent retrospective multicenter cohort study from 2002-2011 of the use of ondansetron in pediatric emergency room settings found that ondansetron use increased substantially from 0.11% in 2002 to 42.2% in 2011. Unfortunately there was only a small decrease in the percentage of patients who received IV hydration (18.7% to 17.8%) and hospital admissions increased over the same study period (6.0% to 6.7%). The authors have several ideas as to why this may occur and state “Our findings highlight the need to focus efforts to administer ondansetron to children at greatest risk for oral rehydration failure.”

Learning Point
According to the European guidelines, ondansetron “…may be effective in young children with vomiting related to AGE. Before a final recommendation is made, a clearance on safety in child is however, needed.” This could be given orally or by IV. The Canadian Pediatric Society recommends a single dose be considered for children 6 months – 12 years with emesis caused by AGE plus having mild to moderate dehydration or having failed oral rehydration therapy. A known side effect of ondansetron is diarrhea, therefore it is not recommended for AGE that is primarily due to diarrhea. Patients with electrolyte abnormalities such as hypomagnesemia and hypokalemia may have increased risk of prolongation of the QT interval when receiving ondansetron.

Questions for Further Discussion
1. How has the rotavirus vaccine changed the epidemiology of gastroenteritis in industrialized nations?
2. What causes chronic diarrhea in the pediatric age group?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Evidence-based medicine information on this topic can be found at SearchingPediatrics.com, the National Guideline Clearinghouse and the Cochrane Database of Systematic Reviews.

Information prescriptions for patients can be found at MedlinePlus for this topic: Gastroenteritis

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

To view videos related to this topic check YouTube Videos.

A Cheng. Emergency department use of oral ondansetron for acute gastroenteritis-related vomiting in infants and children. Canadian Paediatric Society, Acute Care Committee.
Paediatr Child Health 2011;16(3):177-9.

Fedorowicz Z, Jagannath VA, Carter B. Antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents. Cochrane Database Syst Rev. 2011 Sep 7;(9):CD005506

Freedman SB, Hall M, Shah SS, Kharbanda AB, Aronson PL, Florin TA, Mistry RD, Macias CG, Neuman MI.
Impact of increasing ondansetron use on clinical outcomes in children with gastroenteritis. JAMA Pediatr. 2014 Apr;168(4):321-9.

Keren R. Ondansetron for acute gastroenteritis: a failure of knowledge translation. JAMA Pediatr. 2014 Apr;168(4):308-9.

Guarino A, Ashkenazi S, Gendrel D, Lo Vecchio A, Shamir R, Szajewska H. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition/European Society for Pediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: update 2014.
J Pediatr Gastroenterol Nutr. 2014 Jul;59(1):132-52.

RxList.com. Ondansetron Clinical Pharmacology.
Available from the Internet at http://www.rxlist.com/zofran-drug/clinical-pharmacology.htm (rev. 11/7/2014, cited 7/13/2015).

Flake ZA, Linn BS, Hornecker JR. Practical selection of antiemetics in the ambulatory setting. Am Fam Physician. 2015 Mar 1;91(5):293-6.

Author

Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa Children’s Hospital