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Approach to the ill-appearing infant (younger than 90 days of age) Authors: Richard J Scarfone, MD, FAAP Christine Cho, MD, MPH, MEd Section Editors: George A Woodward, MD Jan E Drutz, MD Deputy Editor: James F Wiley, II, MD, MPH Contributor Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Nov 2016. | This topic last updated: Sep 26, 2016. INTRODUCTION — The approach to the ill-appearing infant is reviewed here. The evaluation of fever in infants younger than three months of age is discussed elsewhere. (See "Febrile infant (younger than 90 days of age): Outpatient evaluation" and "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm infants".) CAUSES — Although infection is the most likely cause of ill appearance among neonates and young infants, a number of other clinical conditions have similar manifestations (table 1). Infectious causes — Absence of fever does not exclude infection. Young infants with normal or low core temperatures may have serious infections. For example, hypothermia (rectal temperature <36.5°C [97.7°F]) is associated with systemic herpes simplex virus (HSV) infection, and many infants with pertussis are afebrile. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Temperature instability'.) Bacterial infections ●Bacterial sepsis – Infants can develop sepsis from infections such as urinary tract infections (UTIs), bacteremia, meningitis, pneumonia, skin abscess or cellulitis, mastitis, omphalitis, bacterial gastroenteritis, septic arthritis, or osteomyelitis. (See "Febrile infant (younger than 90 days of age): Outpatient evaluation", section on 'Invasive bacterial infection (IBI)'.) Possible pathogens include the following: •In the immediate newborn period, Escherichia coli has become the most common cause of serious bacterial infection. As a result of universal screening of pregnant women, the incidence of Group B streptococcus has declined; Listeria monocytogenes is a rare cause. (See "Febrile infant (younger than 90 days of age): Outpatient evaluation", section on 'Invasive bacterial infection (IBI)'.) •Beyond the first weeks of life, late-onset disease with Group B streptococcus, Escherichia coli, and Listeria monocytogenes may occur, as may infections with Streptococcus pneumoniae, Neisseria meningitidis, and, to a much lesser extent, Haemophilus influenzae type b. (See "Febrile infant (younger than 90 days of age): Outpatient evaluation", section on 'Invasive bacterial infection (IBI)'.) •Community acquired methicillin resistant Staphylococcus aureus (MRSA) is an important pathogen in infants with skin infections or with known exposures. (See "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'CA-MRSA infection' and"Methicillin-resistant Staphylococcus aureus in children: Treatment of invasive infections", section on 'Treatment approach'.) •In young infants, the origins of osteomyelitis and septic arthritis are typically hematogenous. (See"Hematogenous osteomyelitis in children: Epidemiology, pathogenesis, and microbiology", section on 'Pathogenesis' and "Bacterial arthritis: Epidemiology, pathogenesis, and microbiology in infants and children".) Ascending UTIs with pyelonephritis are the most common serious bacterial infections in neonates and young infants. Fewer than 10 percent of these children will have coexisting bacteremia or urosepsis.Escherichia coli causes more than 80 percent of these infections. Clinically, it is not possible to distinguish lower from upper UTI in this age group. A conservative and appropriate approach is to assume pyelonephritis exists among febrile young children with pyuria (see "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Younger children'). Posterior urethral valves (PUV) are obstructing membranous folds within the lumen of the posterior urethra in the newborn male. Male infants with PUV may present with urosepsis associated with findings of failure to thrive, poor urinary stream, straining or grunting while voiding, elevated serum creatinine, and electrolyte abnormalities of chronic kidney disease (eg, metabolic acidosis and hyperkalemia). The diagnosis is made by voiding cystourethrogram (VCUG) that demonstrates the hallmark findings of a dilated and elongated posterior urethra during the voiding phase (image 1 and image 2) when the urethral catheter is no longer present. Cystoscopy confirms the diagnosis. (See "Clinical presentation and diagnosis of posterior urethral valves", section on 'Clinical manifestations' and "Clinical presentation and diagnosis of posterior urethral valves", section on 'Diagnosis'.) Bacterial meningitis among neonates and infants is caused by the same organisms that cause sepsis. The incidence of bacterial meningitis in this age group has been declining because of universal screening and intrapartum antibiotic prophylaxis for Group B streptococcal disease and the introduction of conjugate vaccines against Haemophilus influenza type b and pneumococcus. (See "Bacterial meningitis in the neonate: Clinical features and diagnosis" and "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Epidemiology'.) ●Pertussis – Pertussis is a ubiquitous and highly contagious infection with significant morbidity and mortality for young infants. Pertussis may present as respiratory failure, apnea and/or bradycardia, or a brief resolved unexplained event (BRUE). Symptoms may be nonspecific, including feeding difficulties, tachypnea, and cough. Gagging, vomiting, apnea, cyanosis, and/or bradycardia often develop during paroxysms of cough. (See "Pertussis infection in infants and children: Clinical features and diagnosis", section on 'Infants'.) Pertussis should be suspected (regardless of vaccination status or wheezing) in infants <4 months with a cough illness, usually without significant fever who have (see "Pertussis infection in infants and children: Clinical features and diagnosis", section on 'Infants <4 months'): •Cough that is not improving (of any duration); the cough may or may not be paroxysmal •Rhinorrhea in which the nasal discharge remains watery •Apnea, seizures, cyanosis, vomiting, or poor weight gain •Leukocytosis with lymphocytosis (white blood cell [WBC] count ≥20,000 cells/microL with ≥50 percent lymphocytes) •Pneumonia There should be a low threshold to suspect pertussis in young infants, given the risk of serious complications. Clinical suspicion of pertussis in infants, especially those younger than four months should trigger immediate treatment. Laboratory confirmation should not delay the initiation of treatment. Early diagnosis and prompt treatment, as well as other precautionary measures, are essential to prevention of transmission. (See "Pertussis infection in infants and children: Treatment and prevention", section on 'Management'.) ●Infant botulism – Infants develop botulism from the ingestion of Clostridium botulinum spores (air-borne, soil-borne, or from food), rather than preformed botulinum toxin. The toxin, which impairs impulses at the neuromuscular junction by blocking acetylcholine release, is then produced by organisms that colonize the infant's gastrointestinal (GI) tract. The disease is more common among breast-fed infants. Symptoms initially include hypotonia, constipation and poor feeding and progress to respiratory failure. The diagnosis of infant botulism should be suspected in any infant with acute onset of weak suck, ptosis, decreased activity, or constipation. A presumptive diagnosis should be made based upon the clinical presentation and electromyography while confirmatory stool studies are pending. The diagnosis and treatment of infant botulism are discussed in greater detail separately. (See "Neuromuscular junction disorders in newborns and infants", section on 'Infant botulism'.) Viral infections ●Overwhelming viral infection – Life-threatening viral infections among neonates are most often caused by HSV or enterovirus. •HSV can cause life-threatening disseminated or central nervous system (CNS) infection in the newborn. As many as one-third of these neonates do not have skin vesicles at presentation, and many are afebrile, making the diagnosis more challenging. Infection is acquired during the birthing process and initial symptoms typically appear in the first month of life. The peak incidence of CNS disease is from 10 to 17 days of life. Those with disseminated infection may have earlier clinical manifestations. HSV infection should be suspected in infants up to six weeks of age although HSV infection is uncommon after 28 days of age. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical suspicion'.) The diagnosis should be suspected among infants who have any of the following findings (see"Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations'): -Maternal HSV -Ill-appearance -Hypothermia (rectal temperature <36.5°C) -Vesicular rash -Mucosal ulcers -Seizures or history of seizures -Cerebrospinal fluid (CSF) pleocytosis or red blood cells -Elevated liver enzymes The indications for the empiric use of acyclovir are discussed separately. (See "Neonatal herpes simplex virus infection: Management and prevention", section on 'Indications'.) •Although typically associated with a self-limiting febrile illness that is sometimes accompanied by viral meningitis, certain enteroviral serotypes, such as group B coxsackievirus serotypes 2 to 5 and echovirus 11, may also produce fulminant myocarditis or hepatitis among neonates. The infection is most often acquired from a symptomatic mother in the perinatal period. Symptoms typically develop between three and seven days of life. However, approximately one-third of cases have a biphasic illness with a period of one to seven days of apparent well-being interspersed between the initial symptoms and the appearance of more serious manifestations. (See "Clinical manifestations and diagnosis of enterovirus and parechovirus infections", section on 'Infections in neonates'.) •Evidence of viral myocarditis has been described in association with BRUEs and sudden infant death beyond the neonatal period as well. Myocarditis in children is usually caused by enteroviruses (coxsackie B group) or adenovirus. Infants may present with a fulminant illness characterized by signs of decreased cardiac output, including hypotension, poor pulses, and decreased perfusion. Malignant arrhythmias are common. (See "Clinical manifestations and diagnosis of myocarditis in children".) ●Bronchiolitis with apnea – Young infants, particularly those who are less than one month of age, were born prematurely and/or have congenital heart disease, may develop apnea with bronchiolitis. Some may present with severe apnea and ill appearance before they develop typical signs of bronchiolitis, such as respiratory distress or wheezing. Bronchiolitis is diagnosed clinically. Chest radiographs and laboratory studies are not necessary to make the diagnosis of bronchiolitis and should not be routinely performed in stable children. However, they are frequently warranted in ill-appearing infants to confirm the clinical diagnosis and assess for the extent of lung involvement. (See "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Apnea' and "Bronchiolitis in infants and children: Clinical features and diagnosis", section on 'Diagnosis'.) ●Influenza – The influenza virus is highly contagious resulting in seasonal epidemics. Influenza-like illness is marked by fever and signs of lower respiratory tract disease, such as coughing. Infants may also present with vomiting, poor feeding, or malaise, and along with the elderly, they suffer the greatest morbidity and mortality from complications such as pneumonia and encephalitis. Those with significant comorbidities such as prematurity or pulmonary or cardiac diseases are at greatest risk for adverse outcomes. During influenza season, an evaluation for influenza virus infection should be pursued in all ill-appearing febrile infants and laboratory confirmation is warranted. (See "Seasonal influenza in children: Clinical features and diagnosis", section on 'Clinical features' and "Seasonal influenza in children: Clinical features and diagnosis", section on 'Whom to test'.) Child abuse — Young infants with severe inflicted injury (typically, head injury) often present with altered mental status, seizures, and/or respiratory distress. There is usually no clear history of trauma. Because signs of external injury, such as burns or contusions may be minimal or absent, one must maintain a high-level of suspicion (table 2 and table 3). Key diagnostic considerations include involvement of a multidisciplinary child abuse team, obtaining laboratory studies (eg, complete blood count, electrolytes, liver enzymes, and a urinalysis), a skeletal survey, neuroimaging, and eye examination by an ophthalmologist (See "Child abuse: Evaluation and diagnosis of abusive head trauma in infants and children", section on 'Evaluation' and "Child abuse: Evaluation and diagnosis of abusive head trauma in infants and children", section on 'Diagnosis'.) Surgical conditions ●Malrotation with volvulus – Malrotation develops as a result of an arrest of normal rotation of the embryonic gut. Abnormal mobility of the small bowel, as the result of a narrow mesenteric base, allows the mesentery to twist. Volvulus occurs when small bowel twists around the superior mesenteric artery, causing vascular compromise to large portions of the midgut (figure 1). This leads to ischemia and necrosis of the bowel that can quickly become irreversible. (See "Intestinal malrotation in children", section on 'Embryology and pathogenesis'.) Vomiting, which is almost always yellow or bilious, occurs in >90 percent of newborns with volvulus and is by far the most common presenting symptom of malrotation in infancy. Abdominal distension and tenderness is typically also present on physical examination. A limited upper GI contrast series is the best diagnostic study. (See "Intestinal malrotation in children", section on 'Clinical presentation' and "Intestinal malrotation in children", section on 'Diagnosis'.) ●Pyloric stenosis – Hypertrophy of both the circular and longitudinal muscular layers of the pylorus results in obstruction. This is a common condition estimated to occur in about 1 of 300 live births. (See "Infantile hypertrophic pyloric stenosis", section on 'Etiology'.) Patients typically come to medical attention at three to six weeks of age with a complaint of progressively worsening projectile, non-bilious emesis. Pyloric stenosis is more common in male infants. A heightened clinical awareness and the liberal use of ultrasound to establish the diagnosis has led to less delay in diagnosis and better outcomes. Thus, the classic presentation with a prolonged duration of vomiting and emaciation accompanied by a palpable mass in the right upper quadrant and a hypokalemic metabolic alkalosis on blood chemistries is less common. (See "Infantile hypertrophic pyloric stenosis", section on 'Clinical manifestations'.) ●Incarcerated hernia – An inguinal hernia develops when intraabdominal contents enter the inguinal canal through a patent processus vaginalis (figure 2). An incarceration results when the hernia cannot be reduced back into the intraabdominal cavity. Incarceration can rapidly progress to strangulation, in which hernia contents become ischemic. (See "Overview of inguinal hernia in children", section on 'Definitions'.) Infants with an incarcerated inguinal hernia usually are irritable and crying. Vomiting and abdominal distention may develop, depending on the duration of incarceration and whether or not intestinal obstruction has occurred. Physical examination of children with incarcerated inguinal hernias usually is diagnostic. A firm, discrete inguinal mass, which may extend to the scrotum or labia majora, can be palpated in the groin. The mass usually is tender and often is surrounded by edema with erythema of the overlying skin. The testicle may appear dark blue because of venous congestion caused by pressure on the spermatic cord. (See "Overview of inguinal hernia in children", section on 'Incarcerated mass'.) ●Congenital aganglionic megacolon (Hirschsprung disease) – The majority of patients with Hirschsprung disease (HD) are diagnosed in the neonatal period. Patients present with symptoms of distal intestinal obstruction: bilious emesis, abdominal distension, and failure to pass meconium or stool. The diagnosis can be suggested by a delay in passage of the first meconium (greater than 48 hours of age). By 48 hours of life, 100 percent of normal full-term neonates will pass meconium. By contrast, 50 to 90 percent of infants with HD will fail to pass meconium within the first 48 hours of life. Thus, passage of stool within the first one to two days of life does not exclude the diagnosis. There may be an explosive expulsion of gas and stool after the digital rectal examination (squirt sign or blast sign), which may relieve the obstruction temporarily. The diagnosis is usually supported by contrast enema or anorectal manometry and is established by rectal biopsy. (See "Congenital aganglionic megacolon (Hirschsprung disease)", section on 'Clinical features'.) Affected infants may also present initially with enterocolitis, a potentially life-threatening illness in which patients have a sepsis-like picture with fever, vomiting, diarrhea, and abdominal distension, which can progress to toxic megacolon. Patients with enterocolitis require fluid resuscitation, intravenous antibiotic therapy to cover bowel flora, rectal irrigations, and, in rare cases, an emergency colostomy. A rare complication of HD is volvulus, which can affect the sigmoid and less commonly the transverse colon and cecum. (See "Emergency complications of Hirschsprung disease".) ●Neonatal appendicitis – Neonatal appendicitis has been reported infrequently. The appendix is typically perforated at the time of diagnosis among infants. Symptoms are nonspecific and include lethargy, irritability, poor feeding, and vomiting. Infants often have abdominal distension and signs of sepsis, such as hypotension. (See "Acute appendicitis in children: Clinical manifestations and diagnosis", section on 'Neonates (0 to 30 days)'.) ●Necrotizing enterocolitis (NEC) – NEC is characterized by bowel wall necrosis that may lead to perforation (image 3). It is most common in premature neonates, especially those of very low birth weight. It may rarely occur in full-term infants, usually within the first 10 days of life. Term infants who develop NEC typically have an underlying condition, such as congenital heart disease or protracted diarrhea. Systemic signs are nonspecific and include apnea, respiratory failure, lethargy, poor feeding, temperature instability, or hypotension resulting from septic shock in the most severe cases. (See "Clinical features and diagnosis of necrotizing enterocolitis in newborns".) Congenital heart disease — Infants with previously undiagnosed congenital heart disease who are seriously ill may have one of the following critical congenital heart defects requiring surgery or catheter manipulation before one year of life (table 4) (see "Identifying newborns with critical congenital heart disease" and"Congenital and pediatric coronary artery abnormalities"): ●Left-side obstructive lesions (eg, hypoplastic left heart syndrome, critical aortic stenosis, coarctation of the aorta, or interrupted aortic arch) ●Right-sided obstruction lesions (eg, Tetralogy of Fallot with pulmonary atresia, pulmonary atresia with intact ventricular septum, critical pulmonary stenosis, tricuspid atresia, or severe neonatal Epstein anomaly) ●Transposition of the great arteries ●Truncus arteriosus ●Total anomalous pulmonary venous return ●Anomalous coronary artery Infants with cyanotic or obstructive heart disease, who are dependent on blood flow through the ductus arteriosus (DA) for pulmonary or systemic circulation, develop severe symptoms as the DA closes over several days to several weeks of life (table 4). Depending upon the specific cardiac lesion and the delay in seeking care, infants may present with some combination of poor feeding, poor weight gain, respiratory distress, cyanosis, shock, acidosis, and congestive heart failure. Obstructive lesions manifested as respiratory distress, shock, and cyanosis may mimic sepsis. (See "Identifying newborns with critical congenital heart disease", section on 'Clinical features'.) The more common forms of cyanotic congenital heart disease may be clinically distinguished from each other and other causes of central cyanosis based upon the physical examination, chest radiography, and electrocardiography (table 5). The hyperoxia test is also used to differentiate cyanotic congenital heart disease from cyanosis due to respiratory disease. Left-sided obstructive lesions often present with diminished femoral pulses compared to the right brachial pulse and right upper extremity blood pressure greater than lower extremity blood pressure. Echocardiography confirms the diagnosis and determines the underlying cardiac anatomy and function. Initial management of the newborn or young infants with cyanotic heart disease is discussed separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Initial management'.) Patients with uncorrected ductal dependent lesions and ill-appearance may benefit from the administration of prostaglandin E1. (See 'Initial stabilization' below.) Congenital adrenal hyperplasia — Congenital adrenal hyperplasia (CAH) is a group of inherited disorders of impaired cortisol synthesis. More than 95 percent of cases are due to 21hydroxylase deficiency, which classically manifests in infancy as virilization and adrenal insufficiency. Male infants are usually more difficult to recognize and may present with adrenal crisis. Adrenal crisis typically develops within the first few days to weeks of life. Clinical manifestations include vomiting, diarrhea, hypovolemia, hyponatremia, hyperkalemia, hypoglycemia, and hypotension (table 6). Female infants may manifest masculinization of the external genitalia. (See "Causes and clinical manifestations of primary adrenal insufficiency in children", section on 'Adrenal crisis'.) A rapid overview provides the initial steps in the diagnosis and treatment of CAH (table 7). Inborn errors of metabolism — IEM should be suspected in all ill-appearing young infants. General laboratory evaluation can help to distinguish among the types of metabolic conditions and help guide specialized testing as shown in the tables (table 8 and table 9). These studies also help to exclude metabolic disease. (See "Inborn errors of metabolism: Metabolic emergencies", section on 'Clinical presentations' and"Inborn errors of metabolism: Metabolic emergencies", section on 'Evaluation of specific critical presentations'.) Although individual defects are uncommon in the general population, inborn errors of metabolism (IEM) account for a significant portion of disease among infants. Testing for IEM may be included in newborn screening tests. However, infants can present before the results are reported. Several categories of IEM may present with an acute metabolic crisis that is triggered by circumstances such as intake of protein or certain carbohydrates or infection such as amino acid disorders, organic acidemias, urea cycle disorders, disorders of carbohydrate metabolism, fatty acid oxidation defects, and mitochondrial disorders. (See "Inborn errors of metabolism: Metabolic emergencies".) The deterioration typically occurs after a period of apparent well-being. Measurement of blood glucose, urine ketones, serum lactate, acid-base status (venous or arterial blood gas), and ammonia can provide an early indication of the presence and type of IEM (table 9). As an example, newborns with urea cycle disorders or organic acidemias generally present with an acute, severe illness characterized by lethargy, poor feeding, vomiting, and shock, with hyperammonemia and profound acidosis. Switching from breast milk to regular formula with the accompanying increase in dietary protein is often an inciting event. (See "Urea cycle disorders: Clinical features and diagnosis".) Galactosemia is notable for its association with urosepsis, usually caused by Escherichia coli and causes metabolic acidosis, reducing substances in the urine, glycosuria, and conjugated or unconjugated hyperbilirubinemia (See "Galactosemia: Clinical features and diagnosis", section on 'Classic galactosemia'.) Cystic fibrosis — Cystic fibrosis may present with meconium ileus, pneumonia, or severe hyponatremic dehydration in an infant, although symptomatic presentations are much less common in regions with newborn screening programs. The diagnosis is based upon clinical findings with biochemical or genetic confirmation (algorithm 1). (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Presentation' and "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Diagnosis'.) Acquired glucose or electrolyte disturbance — Several conditions can cause symptomatic hypoglycemia or abnormalities of sodium or calcium: ●Hypoglycemia – Several factors place infants at increased risk for hypoglycemia (plasma glucose value of ≤40 mg/dL [2.22 mmol/L]). These include low muscle mass, diminished glycogen storage capacity, immaturity of gluconeogenesis and ketogenesis, increased glucose demand, and decreased oral intake during times of stress. Hypoglycemia can be caused by various metabolic, endocrinologic, toxic, and infectious etiologies so its discovery warrants further diagnostic evaluation. Timely recognition by rapid blood glucose testing and treatment with glucose infusion is crucial because prolonged and/or severe hypoglycemia can precipitate seizures and/or permanent brain damage. (See "Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".) ●Hyponatremia – Hyponatremia usually occurs as the result of water intoxication (intake of excessive amounts of free water), syndrome of inappropriate antidiuretic hormone secretion, or from excessive renal losses (such as with congenital adrenal hyperplasia). Occasionally, infants with cystic fibrosis may present with hyponatremic dehydration. Young infants with hyponatremia may develop lethargy or seizures, and the seizures may be refractory to anticonvulsants until the underlying metabolic derangement is corrected. (See "Fluid and electrolyte therapy in newborns", section on 'Hyponatremia'.) ●Hypernatremia – Causes of hypernatremia (150 mEq/L or more) include sodium poisoning, excessive loss of free water (as can occur with diabetes insipidus), or loss of water in excess of sodium losses. Severe hypernatremic dehydration has been reported in association with breast feeding difficulties. Lethargy, irritability, seizures, and/or coma may occur with hypernatremia. (See "Fluid and electrolyte therapy in newborns", section on 'Hypernatremia'.) ●Hypocalcemia – Severe hypocalcemia presents with increased neuromuscular irritability. Such infants are jittery and often have muscle jerking that is induced by environmental noise or other stimuli. Generalized or focal clonic seizures may occur. Rare presentations include inspiratory stridor caused by laryngospasm, wheezing caused by bronchospasm, or vomiting possibly resulting from pylorospasm. The diagnosis is made by identification of a low serum ionized calcium (<1 mmol/L). A variety of genetic and acquired conditions may can cause hypocalcemia (table 10) and require further evaluation as discussed separately. (See "Etiology of hypocalcemia in infants and children".) Other conditions ●Arrhythmias – Arrhythmias, of which supraventricular tachycardia (SVT) is the most common, may go unrecognized. Initial signs are nonspecific and the infant typically tolerates the rapid heart rate. Episodes of SVT are usually paroxysmal and characterized by abrupt onset and termination. The heart rate is typically 220 to 280 beats per minute (bpm) and on ECG, patients exhibiting SVT have no beat to beat variability and little variability in rate, and the QRS interval is typically narrow (<80 msec). If SVT is persistent, the infant eventually develops congestive heart failure. (See "Supraventricular tachycardia in children: AV reentrant tachycardia (including WPW) and AV nodal reentrant tachycardia", section on 'Clinical features' and "Supraventricular tachycardia in children: AV reentrant tachycardia (including WPW) and AV nodal reentrant tachycardia", section on 'Heart failure'.) ●Toxic exposures — Young infants may rarely become ill due to the following toxic exposures: •Iatrogenic overdose of medications – The clinician should obtain a careful history of all medications (including over-the-counter, naturopathic, and herbal supplements) and dosages given to the infants. Because oral medications for infants are in liquid form, it is important to check the volume given and the drug concentration. Dosage errors with severe toxicity have been described with multiple medications including acetaminophen, hyoscyamine (anticholinergic toxicity), methadone (for treatment of neonatal abstinence) and metoclopramide [1,2]. Topical medications that contain local anesthetics (eg, eutectic mixture of lidocaine [EMLA], tetracaine, or benzocaine) are readily absorbed through the skin of young infants and can cause seizures, methemoglobinemia, or cardiac arrhythmias when applied in excess. (See "Topical anesthetics in children" and "Subcutaneous infiltration of local anesthetics", section on 'Systemic toxicity'.) •Malicious drug exposure – Ethanol and drugs of abuse (eg, heroin, cocaine, and amphetamines) may be given maliciously to a young infant [1]. Furthermore, medication administration can be used by perpetrators of medical child abuse to elicit symptoms. (See "Medical child abuse (Munchausen syndrome by proxy)", section on 'Perpetrator actions'.) Malicious drug exposure should be suspected in all young infants with lethargy, seizures, or a complicated medical presentation in whom initial evaluation does not provide an explanation. Initial investigations should include a blood ethanol level and a urine drug screen, preferable close in time to initial presentation. However, negative results do not exclude intentional drug overdose. Consultation with a medical toxicologist is warranted to guide further specific testing. •Ingestion of substances in breast milk – Toxicity has been described for breastfeeding infants whose mothers have used drugs of abuse (eg, heroin, cocaine, phencyclidine, and marijuana) and, rarely, maternal medications [3,4]. Maternal history of drug use and determination of all substances being used by a breastfeeding mother is essential to establishing this toxic exposure. (See "Infants of mothers with substance use disorder", section on 'Breastfeeding'.) •Exposure to environmental toxins – Environmental exposures most frequently associated with ill appearance in young infants include: -Methemoglobinemia – Methemoglobinemia has been described in young infants in association with severe diarrheal illness and following exposure to oxidants (such as water or foods high in nitrites and some topical anesthetics) [5,6]. Infants are susceptible to acute methemoglobinemia because of the relative immaturity of the hemoglobin reductase enzyme system that maintains hemoglobin iron in a reduced state. Patients with methemoglobinemia typically are cyanotic or ashen and, like those with cyanotic congenital heart disease, do not improve with supplemental oxygen. In contrast to infants with cyanotic congenital heart disease, however, oxygen saturation as measured with pulse oximetry, is normal or near-normal despite clinical duskiness. In addition, blood samples are dark-red, chocolate, or brownish to blue in color and do not change with the addition of oxygen (figure 3). (See "Clinical features, diagnosis, and treatment of methemoglobinemia".) -Carbon monoxide poisoning – Infants may develop carbon monoxide poisoning as the result of occult exposure from sources such as improperly vented home heating systems or automobile exhaust fumes [7,8]. The diagnosis may be difficult to make without a history of exposure or symptomatic contacts. Presenting symptoms include lethargy and irritability. Because of their high oxygen consumption, young infants may be the first to display symptoms. (See "Carbon monoxide poisoning".) ●Acute bilirubin encephalopathy – Unconjugated bilirubin is a neurotoxin, which, at very high levels, can cause encephalopathy with permanent neurologic sequelae (kernicterus). Term infants may develop bilirubin neurotoxicity when total serum bilirubin concentrations exceed 25 mg/dL (513 micromol/L). Infants who are at increased risk for ABE include those who are <37 weeks gestation, breastfed, have hemolytic disease, and/or are discharged home before 48 hours. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Neurologic manifestations'.) Acute bilirubin encephalopathy typically progresses through three phases (see "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Acute bilirubin encephalopathy'): •In the early phase, the clinical signs may be subtle. The infant is sleepy but arousable, and when aroused has mild to moderate hypotonia and a high-pitched cry. •If there is no intervention, the intermediate phase evolves with progression and persistence of hyperbilirubinemia. The infant can be febrile, lethargic with a poor suck, or irritable and jittery with a strong suck. The cry can be shrill and the infant is difficult to console. Mild to moderate hypertonia develops, beginning with backward arching of the neck (retrocollis) and trunk (opisthotonos) with stimulation. An emergent exchange transfusion at this stage might prevent permanent bilirubin-induced neurologic dysfunction. •The advanced phase is characterized by apnea, inability to feed, fever, seizures, and a semicomatose state that progresses to coma. Hypertonicity presents as persistent retrocollis and opisthotonos with bicycling or twitching of the hands and feet. The cry is inconsolable, or may be weak or absent. Death is due to respiratory failure or intractable seizures. The diagnosis is based upon elevated indirect bilirubin for age (calculator 1) in association with these clinical findings. ●Kawasaki disease – Kawasaki disease (KD) is rare among young infants. However, in this age group, the presentation is frequently incomplete or atypical. As a result, patients are at increased risk for coronary artery (CA) aneurysms, primarily because of delay in treatment. The diagnosis should be considered in any child under age six months with five or more consecutive days of unexplained fever. (See "Kawasaki disease: Epidemiology and etiology", section on 'Epidemiology' and "Kawasaki disease: Clinical features and diagnosis", section on 'Clinical manifestations'.) In patients with incomplete findings of KD (ie, fever with less than four additional features (table 11)), elevated WBC and platelet counts, transaminases, and acute phase reactants, as well as anemia and pyuria, are suggestive. Echocardiogram (ECHO) should be performed in these patients. The demonstration of CA aneurysms on ECHO may be seen in up to 10 percent of children who never meet criteria for KD. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Diagnosis'.) INITIAL STABILIZATION — Ill-appearing infants typically require stabilization and empiric therapy based upon an initial rapid assessment with supportive studies prior to a comprehensive evaluation. Key interventions include: ●Provide supplemental 100 percent oxygen and perform basic airway maneuvers (eg, positioning, headtilt/chin lift, or insertions of artificial airways) as needed. (See "Basic airway management in children", section on 'Noninvasive relief of obstruction'.) ●Secure airway in patients at risk (apnea, no gag, altered mental status [eg, lethargy, coma, or seizures]) by rapid sequence intubation. (See "Rapid sequence intubation (RSI) in children", section on 'Rapid overview'.) ●Support ventilation, as needed, using bag-valve mask ventilation, noninvasive ventilation, or endotracheal intubation with mechanical ventilation. (See "Basic airway management in children", section on 'Bag-mask ventilation' and "Noninvasive ventilation for acute and impending respiratory failure in children".) ●Establish vascular or intraosseous access and obtain initial blood studies. (See 'Ancillary studies for infectious etiologies' below.) ●Identify and treat arrhythmias (eg, supraventricular tachycardia) (algorithm 2). ●Give an initial rapid infusion of isotonic crystalloid solutions in patients with hemodynamic compromise; the volume and speed of infusion is determined by the underlying cause (eg, more rapidly and greater volume [eg, 20 mL/kg repeated two to three times] in patients with hypovolemic or septic shock, more slowly and less volume [eg, 5 to 10 mL/kg]) in patients with suspected congenital heart disease. (See "Initial evaluation of shock in children" and "Initial management of shock in children".) ●In infants with altered mental status (eg, lethargy, coma, or history of seizures), obtain a rapid blood glucose and treat hypoglycemia as needed (table 12). (See "Approach to hypoglycemia in infants and children", section on 'Immediate management'.) ●In infants with active seizures, obtain rapid blood glucose and point of care electrolyte studies and administer anticonvulsants (eg, midazolam or lorazepam [phenobarbital if neonatal seizures]). Treat underlying causes (eg, hypoglycemia, hyponatremia, hypocalcemia, or inborn errors of metabolism). (See'Seizures' below and "Management of convulsive status epilepticus in children", section on 'Initial treatment'and "Treatment of neonatal seizures".) ●Measure rectal temperature and provide warming as needed (table 13). Provide active external rewarming (eg, heat lamp) to prevent hypothermia in infants with normal body temperature. (See "Hypothermia in children: Management", section on 'Treatment of mild hypothermia' and "Hypothermia in children: Management", section on 'Treatment of moderate or severe hypothermia'.) Rapid assessment of critically ill infants is discussed in greater detail separately. (See "Pediatric advanced life support (PALS)", section on 'Assessment'.) EMPIRIC THERAPY — Empiric management of ill-appearing infants is frequently required before a definitive diagnosis can be established and may be life-saving. In this situation, the emergency clinician must determine the likelihood that an infant may have the diagnosis, while considering the potential harm of the treatment. Antibiotics — Symptoms of overwhelming infection are often nonspecific in young infants. Once cultures of blood and urine (and cerebrospinal fluid [CSF], if a lumbar puncture can be safely performed) have been obtained, ill-appearing young infants should receive antibiotics unless an alternative diagnosis can be rapidly established and treated (eg, cyanotic congenital heart disease) (table 14). (See "Febrile infant (younger than 90 days of age): Management", section on 'Management'.) Acyclovir — Early treatment with acyclovir is associated with improved outcomes among infants with herpes simplex virus (HSV) infections. However, the definitive diagnosis may depend on culture results or other tests that are not immediately available, such as polymerase chain reaction (PCR) testing. Neonates under 28 days of age who are ill-appearing generally warrant empiric administration of acyclovir, especially if they have any of the following findings (see "Neonatal herpes simplex virus infection: Management and prevention", section on 'Indications'): ●Hypothermia ●Skin, eye, or mucocutaneous vesicles ●Neurologic symptoms such as seizures or lethargy ●CSF pleocytosis with a negative CSF Gram stain ●Red blood cells in CSF ●Thrombocytopenia or disseminated intravascular coagulopathy (DIC) ●Hepatomegaly, ascites, or markedly elevated serum transaminases ●Maternal history of HSV Testing for HSV should be obtained before acyclovir is given. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV'.) Early treatment may also be warranted for ill-appearing infants 29 to 60 days of age who have mucocutaneous vesicles and other findings of HSV infection as described above. Prostaglandin E1 (alprostadil) — For infants with cyanotic or obstructive heart disease who are dependent on blood flow through the ductus arteriosus (DA) for pulmonary or systemic circulation (table 4), severe symptoms can develop when the DA closes over the first several days to weeks of life. Administration of prostaglandin E1 (alprostadil) can reopen the DA and stabilize these infants pending definitive diagnosis and treatment. Structural closure of the DA is usually completed by two to three weeks of age, making the diagnosis of a ductal-dependent cardiac defect unlikely among infants older than 28 days. (See "Clinical manifestations and diagnosis of patent ductus arteriosus in term infants, children, and adults", section on 'Fetal and transitional ductal circulation'.) Indications of a ductal-dependent cardiac lesion include one of the following: ●Failed hyperoxia test, suggesting cyanotic heart disease (see "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Hyperoxia test') OR ●A pulse or blood pressure gradient between the upper and lower extremities, suggesting an obstructive cardiac defect (see "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Blood pressure and pulses') For hypoxic, hemodynamically unstable infants with ductal-dependent congenital heart disease, treatment with prostaglandin E1 (PGE1, alprostadil) to reopen the DA can be life-saving and should be given pending definitive diagnosis and treatment in consultation with a pediatric cardiologist. PGE1 frequently causes apnea; the treating physician should be prepared to intubate the patient. Initiation of PGE1, including recommended dosing, is discussed separately. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1'.) Stress-dose hydrocortisone — An infant with previously undiagnosed congenital adrenal hyperplasia (CAH) may develop adrenal crisis and present as septic-appearing. Adrenal crisis is more common in males with CAH because they lack the physical findings of ambiguous genitalia or clitoromegaly (picture 1) noted at birth in female infants. Specific manifestations of adrenal insufficiency include shock, hyponatremia, hyperkalemia, and hypoglycemia. (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Management in neonates'.) Patients with these findings must promptly receive treatment for hypoglycemia, normal saline fluid boluses for shock, and stress doses of hydrocortisone. Whenever, possible, a blood sample for steroid hormone measurements (most importantly, 17-hydroxyprogesterone) should be obtained prior to hydrocortisone administration. These patients should not receive hypotonic saline to avoid making their hyponatremia worse. Hyperkalemia typically responds rapidly to the mineralocorticoid action of stress dose hydrocortisone. However, specific treatment for hyperkalemia may occasionally be required as noted in the rapid overview (table 15). (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Adrenal crisis'.) EVALUATION — Infants who have respiratory or circulatory compromise must be quickly identified and their conditions stabilized. (See 'Initial stabilization' above.) Once stabilized a careful evaluation is necessary to determine the definitive diagnosis. History Nonspecific symptoms — Nonspecific symptoms such as altered mental status (lethargy or irritability), increased sleepiness, poor feeding, apnea, decreased tone, brief resolved unexplained event (BRUE) or seizures can be indicators of a variety of serious underlying conditions especially for infants who are ill-appearing on presentation. Important aspects of nonspecific symptoms include: ●Infants with inflicted head injury often have nonspecific symptoms or chief complaints (such as seizures, breathing difficulty, vomiting, poor feeding, apnea, or limpness). There is typically no clear history or an inconsistent history of trauma (table 2). (See "Child abuse: Evaluation and diagnosis of abusive head trauma in infants and children", section on 'History'.) ●BRUE is not a specific diagnosis; rather, it describes a "chief complaint" that brings an infant to medical attention. It may be defined as an episode that is frightening to the observer and is characterized by some combination of apnea, color change, change in muscle tone, choking, or gagging. Ill-appearing infants with a history of BRUE may have any of the conditions described above (table 16). (See "Acute events in infancy including brief resolved unexplained event (BRUE)", section on 'Apparent life-threatening event (ALTE)'.) ●Abnormal rhythmic movements may represent seizure activity. Seizures occur more commonly in infancy than at other times during childhood, yet they remain difficult to recognize because generalized tonic-clonic activity typically does not occur. In young infants, seizures frequently accompany hypoxia, hypoglycemia, electrolyte disturbances (eg, hyponatremia, hypernatremia, hypocalcemia), abusive head trauma, sepsis (especially systemic herpes simplex virus [HSV] infection), and inborn errors of metabolism. Neonatal seizures are especially difficult to recognize because they are often subtle and can be hard to differentiate from normal neonatal movement. They present with irregularities of breathing, heart rate, muscle tone, and eye and lip movements (eg, nystagmus, gaze preference, or intermittent lip smacking). Hypoxic-ischemic injury is the most common cause of neonatal seizures. Other causes include infections, metabolic disturbances, trauma, structural brain disease, or drug withdrawal (table 17). Electroencephalogram is diagnostic in many patients. (See "Etiology and prognosis of neonatal seizures".) Specific symptoms — The following complaints are often associated with specific conditions (table 18): ●Fever (rectal temperature >38°C (100.5°F) points to a bacterial or viral infection but may also occur in patients with intracranial bleeding caused by abusive head trauma or bowel perforation due to an underlying surgical condition. (See 'Infectious causes' above and 'Child abuse' above and 'Surgical conditions' above.) ●HSV infection must be considered for an ill-appearing neonate with hypothermia; seizures; vesicular lesions of the skin, eye, or mouth; or whose mother has genital vesicular lesions. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations'.) ●Cough can be associated with pneumonia, bronchiolitis, pertussis, or congenital heart disease. ●Cyanosis, tachypnea and/or diaphoresis with feeding are frequently seen in infants with congenital heart disease. ●Decreased feeding associated with a poor suck and progressive weakness supports the diagnosis of infant botulism. (See 'Bacterial infections' above.) ●Infants who develop projectile vomiting may have pyloric stenosis. ●Bilious vomiting may indicate a bowel obstruction distal to the ligament of Treitz (eg, malrotation with volvulus, congenital aganglionic megacolon (Hirschsprung disease [HD]), or bowel perforation caused by neonatal appendicitis or necrotizing enterocolitis. (See 'Surgical conditions' above.) ●Abdominal distension with infrequent or no stooling suggests bowel obstruction due to surgical conditions, HD, or meconium ileus due to cystic fibrosis. ●An infant who is not moving an extremity may have osteomyelitis, septic arthritis, or a fracture. ●The urine of some infants with inborn errors of metabolism may have an unusual odor (table 19). (See'Inborn errors of metabolism' above.) Other history — Important features of the perinatal history include the following: ●Maternal infections, fever, and Group B streptococcal testing and results ●Mode of delivery ●Prematurity ●Birth asphyxia ●Need for neonatal intensive care ●Length of stay in the newborn nursery Onset of vomiting, tachypnea, seizures, or lethargy in association with switching from breast milk to formula can indicate onset of an acute metabolic crisis due to increased protein intake in an infant with an inborn error of metabolism. (See 'Inborn errors of metabolism' above and "Inborn errors of metabolism: Metabolic emergencies", section on 'Causes of acute metabolic decompensation'.) Finally, the following information provides useful clues to the etiology of the infant's symptoms: ●Fever or ill contacts – Infectious cause ●Stooling patterns – Constipation in infants with Hirschsprung disease (HD), meconium ileus, or infant botulism ●Patient medications – Iatrogenic overdose ●Maternal prescription or recreational drug use for a breastfeeding infant – Unintentional toxic exposure Physical examination — The general appearance typically includes nonspecific features such as irritability, lethargy, poor tone, and decreased activity. A careful physical examination may identify a combination or pattern of clinical features that suggest the etiology of an infant's symptoms (table 20). ●Vital signs – Important features of vital signs include: •Fever points to an infectious cause although lack of fever does not exclude an infectious illness. Fever may also occur in infants with intracranial hemorrhage due to abusive head trauma and bowel perforation from surgical conditions. (See 'Infectious causes' above.) •Hypothermia (rectal temperature <36.5°C [97.7°F]) may occur with sepsis or hypoglycemia. Infants are also more prone to hypothermia caused by environmental exposure. (See "Hypothermia in children: Clinical manifestations and diagnosis", section on 'Pediatric considerations'.) •Pulses and blood pressure measurements should be obtained in both arms and both legs. Diminished pulses and blood pressure in the lower extremities suggest left ventricular outflow obstruction, as occurs with hypoplastic left heart syndrome, critical aortic stenosis, or coarctation of the aorta. (See"Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Blood pressure and pulses'.) •An infant with a heart rate over 220 beats per minute (bpm) probably has a tachyarrhythmia, most commonly supraventricular tachycardia. Sinus tachycardia rarely exceeds 220 bpm. (See"Supraventricular tachycardia in children: AV reentrant tachycardia (including WPW) and AV nodal reentrant tachycardia", section on 'Clinical features'.) ●Head – A bulging fontanel points to increased intracranial pressure secondary to meningitis or head trauma with major intracranial bleeding (eg, child abuse). Increased head circumference (eg, >85thpercentile for age (figure 4 and figure 5)) may also indicate repeated head injuries from abuse with residual hematomas or hydrocephalus. (See "Child abuse: Evaluation and diagnosis of abusive head trauma in infants and children", section on 'Diagnosis'.) ●Respiratory signs – Respiratory signs (such as tachypnea, grunting, or retractions) may be nonspecific. However, rales and/or wheezing suggest lung disease (eg, pneumonia or bronchiolitis) or heart failure. ●Cardiovascular examination – Features of the cardiovascular examination may suggest a congenital defect. Findings to note include (see "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Physical examination' and "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Clinical manifestations'): •Blood pressure gradient between the arms and legs •Weak or absent femoral pulses when compared to brachial pulses •Differential cyanosis by pulse oximetry in the preductal (right hand in infants with a left aortic arch) and postductal (right or left foot) sites •Single second heart sound (table 5) •The presence of a pathologic heart murmur (table 5) which suggests cardiac disease, although the absence of a murmur does not exclude it •A gallop rhythm which typically indicates heart failure ●Abdominal examination – Abdominal distention may be caused by bowel obstruction, but it is a nonspecific finding. A normal abdominal examination does not exclude serious conditions. As an example, in one case series describing children with malrotation, 60 percent of those with volvulus had a normal abdominal examination [9]. Hepatomegaly may arise from congenital heart disease with heart failure or some forms of metabolic disease. (See "Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features", section on 'Organomegaly'.) ●Genital-urinary examination – The presence of an irreducible mass in the scrotum or labia identifies an incarcerated hernia. Ambiguous genitalia, clitoromegaly (picture 1), or a hyperpigmented scrotum may indicate congenital adrenal hyperplasia. (See "Evaluation of the infant with atypical genitalia (disorder of sex development)", section on 'Identifying the category and cause'.) An explosive expulsion of gas and stool after a digital rectal examination (squirt sign or blast sign) in an infant with abdominal distension points to congenital aganglionic megacolon (HD). (See 'Surgical conditions' above.) ●Musculoskeletal examination – An immobile extremity that is painful on passive motion suggestions a fracture or, in infants with a fever or osteomyelitis. Joint swelling with a limited range of motion, warmth and redness is consistent with septic arthritis. ●Neurologic examination – Jitteriness with increased myoclonus exacerbated by loud noises is consistent with hypocalcemia. Conditions associated with seizures or status epilepticus include hypoglycemia, hyponatremia, hypernatremia, child abuse with intracranial hemorrhage, meningitis or encephalitis, or drug exposure. Weak cry, hypotonia, hyporeflexia, diminished or absent gag reflex, ptosis, and weak suck in a previously healthy infant suggest infant botulism. ●Skin – Skin findings may include: •Signs of viral or bacterial infection, such as vesicles, pustules, cellulitis, or abscess formation •Jaundice which may accompany sepsis or acute bilirubin encephalopathy •Acrocyanosis from poor perfusion •Any bruising in a pre-mobile infant is concerning for physical child abuse (see "Physical child abuse: Recognition", section on 'Red flag physical findings') •Central cyanosis that does not respond to supplemental oxygen indicating cyanotic heart disease or methemoglobinemia (see 'Abnormal cardiovascular examination' below) •Hyperpigmentation that points to congenital adrenal hyperplasia Ancillary studies for infectious etiologies — All ill-appearing infants younger than 90 days of age in whom sepsis is suspected warrant the following laboratory studies to evaluate for an infectious cause: ●Rapid blood glucose ●Blood culture ●Complete blood count with differential ●Serum electrolytes ●Ionized calcium ●Serum lactate ●Blood urea nitrogen ●Serum creatinine ●Blood gas (arterial or venous) ●Urinalysis and urine culture (obtained by urethral catheterization) ●Wound culture for bacteria in patients with pustules or a draining skin abscess ●Stool culture for patients with diarrhea ●Cerebrospinal fluid (CSF) for cell count, glucose, protein, Gram stain, bacterial culture and, depending upon clinical findings, polymerase chain reaction (PCR) for HSV and/or enterovirus, and if pleocytosis, viral culture Lumbar puncture (LP) may be deferred for those patients who have respiratory or hemodynamic instability or for whom an alternative diagnosis (such as congenital heart disease or volvulus) is quickly established. However, antibiotic administration should not be delayed in patients in whom LP is deferred. ●For patients with signs of septic shock such as altered mental status, poor perfusion, or hypotension (see"Systemic inflammatory response syndrome (SIRS) and sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Septic shock: Rapid recognition and initial resuscitation in children", section on 'Rapid recognition'): •Prothrombin time (PT), partial thromboplastin time (aPTT), international normalized ratio (INR) •Fibrinogen and D-dimer •Serum total bilirubin and alanine aminotransferase ●For patients with signs of pneumonia (fever, tachypnea, and/or rales) – Chest radiograph; note that chest radiograph is not indicated in stable patients with clinical findings of bronchiolitis ●For patients with mucocutaneous vesicles, seizure, CSF pleocytosis with a negative Gram stain, or risk factors for vertical transmission of HSV infection (see "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV'): •Surface cultures of conjunctivae, mouth, nasopharynx, and rectum •Swabs and scraping of skin vesicles or mucous membrane lesions for cultures and direct fluorescent antibody tests •PCR of blood and CSF •Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) •Total and direct bilirubin ●Wound culture for bacteria in patients with pustules or a draining skin abscess is warranted. TARGETED EVALUATION — A systematic approach to the emergency evaluation of an illappearing young infant (including a focused history, careful physical examination, and selected ancillary studies) can often identify those with a condition other than sepsis that requires emergency evaluation and treatment (table 1 andtable 18 and table 20). In many patients, confirmation of an alternative diagnosis takes time and obtaining laboratory studies for sepsis is also performed. (See 'Ancillary studies for infectious etiologies' above.) Respiratory distress — Patients with respiratory distress should have a chest radiograph, blood gas (venous or arterial), and pulse oximetry obtained. Abnormalities on the radiograph may indicate the presence of pneumonia, bronchiolitis, pertussis infection, viral pneumonitis, congenital heart disease, or pulmonary edema from heart failure. Blood gas measurement identifies the presence of a metabolic acidosis that may warrant further evaluation. (See 'Metabolic acidosis'below.) Abnormal cardiovascular examination — Patients with an abnormal cardiovascular examination should undergo electrocardiogram (ECG), chest radiograph, and, for patients who also have cyanosis, the hyperoxia test. (See 'Cyanosis' below.) These studies frequently can identify specific congenital heart lesions (table 5). They also can provide supportive evidence for the presence of supraventricular tachycardia or other arrhythmias, myocarditis, pericarditis, or anomalous coronary arteries. Echocardiogram (ECHO) by a pediatric cardiologist provides confirmation of structural cardiac anomalies. Cyanosis — For infants with cyanosis, the hyperoxia test can help to distinguish cardiac from pulmonary disease. Oxygen saturation is measured using pulse oximetry before and while the infant is breathing 100 percent oxygen. Oxygen saturation should improve by at least 10 percent for pulmonary causes of cyanosis. An abnormal or equivocal response suggests cardiac disease and must be verified by measurement of an arterial blood gas, taken from the right radial artery, while the infant is breathing 100 percent oxygen. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Hyperoxia test'.) Cyanosis that improves with supplemental oxygen usually indicates lung disease, most commonly pneumonia. Pulmonary edema from acyanotic congenital heart lesions, cardiomyopathy, or myocarditis are additional considerations. These patients typically have abnormal cardiovascular examinations. (See 'Abnormal cardiovascular examination' above.) Central cyanosis that does not improve during the hyperoxia test occurs with cyanotic congenital heart disease and methemoglobinemia. Infants with methemoglobinemia typically have a sudden onset of cyanosis and oxygen saturation levels that are higher than would be expected based on the degree of cyanosis while those with cyanotic congenital heart disease are cyanotic at birth. Evaluation should be tailored to the most likely etiology of central cyanosis as follows: ●Congenital cyanotic heart disease: •Electrocardiogram – ECG findings may suggest a specific anatomic lesion (table 5). A myocardial ischemia pattern may identify infants who have aberrant coronary arteries. (See "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Postnatal diagnosis' and"Congenital and pediatric coronary artery abnormalities", section on 'Diagnosis'.) •Chest radiograph – Key findings include cardiomegaly, abnormal heart shape, increased or decreased pulmonary blood flow, or pulmonary edema (table 5). •Echocardiogram – An ECHO by a pediatric cardiologist provides the definitive diagnosis for infants with congenital heart disease and should be performed emergently in critically ill infants. ●Methemoglobinemia (see "Clinical features, diagnosis, and treatment of methemoglobinemia", section on 'Diagnosis'): •Patients with methemoglobinemia may appear cyanotic or dusky but have normal or near-normal oxygen saturations as measured by pulse oximetry. •Blood from patients with methemoglobinemia is dark-red, chocolate, or brownish to blue in color and does not change when exposed to oxygen (figure 3). •Methemoglobinemia is strongly suggested when there is clinical cyanosis in the presence of a calculated normal arterial pO2 (PaO2) as obtained by arterial blood gases. Arterial blood gas analysis is deceptive because the partial pressure of oxygen is normal in subjects with excessive levels of methemoglobin. •The diagnosis is confirmed by direct measurement of blood methemoglobin or cooximetry on a venous or arterial sample. Seizures — In addition to evaluation for central nervous system infection as described above (see 'Ancillary studies for infectious etiologies' above), young infants with seizures also warrant the following studies: ●Rapid blood glucose ●Ionized calcium ●Serum phosphate ●Serum magnesium ●Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ●Plasma ammonia, additional studies for inborn errors of metabolism based upon degree of suspicion as shown in the table (table 8) ●Blood ethanol level if intentional poisoning is suspected ●Rapid urine screen for drugs of abuse if intentional poisoning is suspected ●Neuroimaging (eg, cranial ultrasound, computed tomography, or magnetic resonance imaging) in patients without hypoglycemia or electrolyte abnormalities as the likely cause Seizures are common in infants with inborn errors of metabolism (IEM) and may be associated with sudden decompensation with diet change or marked metabolic acidosis, hyperammonemia with respiratory alkalosis, urinary ketones or hypoglycemia (table 9). Further evaluation for IEM depends upon the presenting features as shown in the table (table 8). (See "Inborn errors of metabolism: Metabolic emergencies" and "Inborn errors of metabolism: Identifying the specific disorder".) A skeletal survey (plain films of all bones) to screen for old or new fractures, neuroimaging, and retinal examination by an ophthalmologist are indicated in infants with suspected child abuse. (See "Physical child abuse: Diagnostic evaluation and management", section on 'Approach'.) Vomiting or abnormal abdominal examination — Vomiting is commonly associated with gastrointestinal (GI) infections (diarrhea is frequently also present), urinary tract infections, pneumonia, increased intracranial pressure, and inborn errors of metabolism. Plain films of the abdomen (AP and left lateral decubitus views) are indicated for infants with findings of possible surgical conditions such as abdominal distention, tenderness, or vomiting (especially projectile or bilious vomiting) to exclude perforation or abnormalities that may be seen with necrotizing enterocolitis (NEC) (eg, pneumatosis intestinalis [gas within the intestinal wall], portal venous gas, or pneumoperitoneum (image 3)). With malrotation and pyloric stenosis, there may be duodenal or gastric distention with a paucity of air distally. Hirschsprung disease (HD) may present with megacolon or signs of large bowel obstruction. Cystic fibrosis may demonstrate a meconium ileus (image 4). Patients with perforation noted on plain abdominal radiographs require emergency consultation and further management guided by a pediatric surgeon. Hemodynamically stable young infants with bilious emesis but no sign of GI perforation on plain radiographs should undergo upper GI (UGI) contrast studies with small bowel follow through. A duodenal bulb that overlies the spine and/or a medially directed cecum suggests malrotation (image 5 and image 6). A corkscrew appearance in the small bowel can be seen with volvulus (image 7). (See "Intestinal malrotation in children", section on 'Diagnosis'.) An abdominal ultrasound is the preferred study to detect pyloric stenosis (image 8) suggested by projectile nonbilious vomiting. (See "Infantile hypertrophic pyloric stenosis", section on 'Diagnosis'.) Contrast enema helps support the diagnosis of congenital aganglionic megacolon (HD) (image 9) and confirms the diagnosis of meconium ileus (image 10). (See "Congenital aganglionic megacolon (Hirschsprung disease)", section on 'Diagnosis' and "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Meconium ileus (MI)'.) For management of these conditions, refer to UpToDate topic reviews. Musculoskeletal findings — Infants who are not moving an extremity or have swollen extremities or joints should have a plain radiograph of the affected extremity. Infants with fractures require consultation with a multidisciplinary child abuse team, skeletal survey, screening laboratory studies, neuroimaging, and eye examination by an ophthalmologist. (See "Physical child abuse: Diagnostic evaluation and management".) Inflammatory markers (eg, erythrocyte sedimentation rate and C-reactive protein) and when appropriate, joint fluid, should be obtained for analysis in patients with signs of bone or joint infection along with more specific imaging guided by a pediatric radiologist or orthopedist (table 21). (See "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Birth to three months' and "Bacterial arthritis: Clinical features and diagnosis in infants and children".) Bruises — Any bruising in a young infant without a history of trauma is concerning for child abuse and is an indication for a skeletal survey, neuroimaging, retinal examination by an ophthalmologist, and screening laboratory studies as well as consultation with a multidisciplinary child abuse team (table 3). In many parts of the world, a report to appropriate governmental authorities is also required. (See "Physical child abuse: Diagnostic evaluation and management".) Jaundice — Jaundiced infants should have a total and direct serum bilirubin and additional studies based upon whether the jaundice is in the neonatal or beyond the neonatal period. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Systematic approach' and "Evaluation of jaundice caused by unconjugated hyperbilirubinemia in children", section on 'Diagnostic approach'.) Ill infants who have high unconjugated (indirect) hyperbilirubinemia may have acute bilirubin encephalopathy (calculator 1). (See 'Other conditions' above.) Conjugated hyperbilirubinemia suggests sepsis, inborn errors of metabolism, or liver disease (eg, herpes simplex virus [HSV] hepatitis). (See "Evaluation of jaundice caused by unconjugated hyperbilirubinemia in children", section on 'Causes of unconjugated hyperbilirubinemia'.) Abnormal studies — Young infants with nonspecific features require ancillary studies to identify the underlying cause. Abnormal cerebrospinal fluid — Infants with CSF pleocytosis usually have meningitis or encephalitis. HSV infection must be considered when there is CSF pleocytosis with no organisms on gram stain. Child abuse is of concern when CSF red blood cells are prominent despite an atraumatic lumbar puncture. Infectious etiologies of specific CSF abnormalities is provided in the table (table 22). (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Interpretation of CSF' and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Clinical manifestations' and "Bacterial meningitis in the neonate: Clinical features and diagnosis", section on 'Lumbar puncture'.) Abnormal chest radiograph — Lung infiltrates on a chest radiograph may represent infections (such as pneumonia or bronchiolitis) or heart failure. Infants with cardiomegaly or abnormal cardiac silhouettes may have congenital heart disease or myocarditis. Pyuria — An abnormal urinalysis, particularly with pyuria, suggests pyelonephritis and possible urosepsis in the ill-appearing infant. (See "Urinary tract infections in infants and children older than one month: Clinical features and diagnosis", section on 'Microscopic exam'.) Urosepsis may be associated with galactosemia or posterior urethral valves. Patients with clinical features of either of these diagnoses warrant further specific testing. (See "Galactosemia: Clinical features and diagnosis", section on 'Diagnosis' and "Clinical presentation and diagnosis of posterior urethral valves", section on 'Diagnosis'.) Metabolic acidosis — Unexplained and severe metabolic acidosis suggests inborn errors of metabolism. Abnormal blood chemistries — Abnormalities in blood chemistries may help to identify a specific condition. In addition, many of these abnormalities require urgent treatment. ●Infants who are seriously ill are frequently hypoglycemic (table 12). Severe hypoglycemia is also associated with shock, congenital adrenal hyperplasia, and inborn errors of metabolism. (See"Pathogenesis, screening, and diagnosis of neonatal hypoglycemia".) ●Acidosis is a nonspecific consequence of many disorders: •Hypoxemia from pneumonia, bronchiolitis, or heart failure •Septic shock and/or dehydration •CAH (table 23) •Inborn errors of metabolism •Congenital heart disease •Methemoglobinemia •Carbon monoxide poisoning •NEC •Any surgical condition resulting in perforation or bowel ischemia ●Infants with pyloric stenosis may develop hypochloremic alkalosis from loss of gastric hydrochloric acid as the result of persistent vomiting. (See "Infantile hypertrophic pyloric stenosis", section on 'Classic presentation'.) ●Hyponatremia may develop as the result of excessive vomiting (eg, pyloric stenosis), water intoxication (intake of excessive amounts of free water), syndrome of inappropriate antidiuretic hormone secretion, or from excessive sodium losses (such as renal losses with CAH or losses from the skin with cystic fibrosis). (See "Fluid and electrolyte therapy in newborns", section on 'Hyponatremia' and 'Acquired glucose or electrolyte disturbance' above.) ●Hypernatremia typically occurs as the result of sodium (salt) poisoning, excessive loss of free water (as can occur with diabetes insipidus), or loss of water in excess of sodium losses. (See "Fluid and electrolyte therapy in newborns", section on 'Hypernatremia' and 'Acquired glucose or electrolyte disturbance' above.) ●Hypocalcemia may occur in the first few days of life in infants with prematurity, birth asphyxia, intrauterine growth restriction, or mother with diabetes. Hypocalcemia occurring within the first week of life is associated with hypoparathyroidism and high phosphate intake. (See "Neonatal hypocalcemia".) For infants outside of the first week of life, hypocalcemia may occur due to genetic conditions, autoimmune disease, sepsis, and renal or hepatic dysfunction. (See "Etiology of hypocalcemia in infants and children".) ●Hyperammonemia is a characteristic finding in urea cycle defects, organic acidemias, fatty acid oxidation defects, and liver dysfunction (algorithm 3). SUMMARY AND RECOMMENDATIONS ●Ill-appearing infants typically require stabilization and empiric therapy based upon an initial rapid assessment with supportive studies prior to a comprehensive evaluation (see 'Initial stabilization' above and 'Empiric therapy' above): •Once cultures of blood and urine (and cerebrospinal fluid [CSF], if possible) have been obtained, ill-appearing young infants should receive antibiotics unless an alternative diagnosis can be rapidly established and treated (eg, cyanotic congenital heart disease) (table 14). (See "Febrile infant (younger than 90 days of age): Management", section on 'Ill-appearing' and "Febrile infant (younger than 90 days of age): Management", section on 'Neonates (28 days of age and younger)'.) •Neonates (infants younger than 28 days of age) who have mucocutaneous vesicles, seizures, CSF pleocytosis with a negative Gram stain, or maternal herpes simplex virus (HSV) infection should receive acyclovir empirically. HSV testing should be obtained prior to treatment. Although HSV infection is much less common in older infants, empiric acyclovir administration may also be warranted for infants 29 to 60 days of age with these clinical features. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis' and "Neonatal herpes simplex virus infection: Management and prevention", section on 'Acyclovir therapy'.) •For hypoxic, hemodynamically unstable infants with ductal-dependent congenital heart disease (table 4), treatment with prostaglandin E1 (PGE1, alprostadil) to reopen the DA can be life-saving and should be given pending definitive diagnosis and treatment in consultation with a pediatric cardiologist. Initiation of PGE1, including recommended dosing, is discussed separately. (See 'Prostaglandin E1 (alprostadil)' above and "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1'.) •Critically ill infants with signs of adrenal crisis (shock, hyponatremia, hyperkalemia, and hypoglycemia) must promptly receive treatment for hypoglycemia, normal saline fluid boluses for shock, and stress doses of hydrocortisone (table 7). Whenever, possible, a blood sample for steroid hormone measurements (most importantly, 17hydroxyprogesterone) should be obtained prior to hydrocortisone administration. (See 'Stress-dose hydrocortisone' above and "Treatment of adrenal insufficiency in children", section on 'Adrenal crisis'.) ●Ill-appearing young infants often have an infectious cause. However, the physician should carefully evaluate for other important conditions (table 1). (See 'Causes' above.) ●Historical features, physical findings, and initial ancillary studies may provide clues to a specific diagnosis (table 18 and table 20). (See 'Evaluation' above.) ●After initial stabilization and provision of empiric therapy as needed, a targeted evaluation based upon a detailed history and physical examination frequently identifies the underlying condition and guides definitive therapy. (See 'Targeted Evaluation' above and 'Abnormal studies' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. Tzimenatos L, Bond GR, Pediatric Therapeutic Error Study Group. Severe injury or death in young children from therapeutic errors: a summary of 238 cases from the American Association of Poison Control Centers. Clin Toxicol (Phila) 2009; 47:348. Kang AM, Brooks DE. US Poison Control Center Calls for Infants 6 Months of Age and Younger. Pediatrics 2016; 137:e20151865. 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