Approach to the ill-appearing infant (younger than 90 days of age)

INTRODUCTION — The approach to the ill-appearing young infant is reviewed here. The causes of ill appearance and evaluation of fever in infants <90 days of age is discussed separately:

●(See "Ill-appearing infant (younger than 90 days of age): Causes".)

●(See "The febrile infant (29 to 90 days of age): Outpatient evaluation".)

●(See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates".)

TERMINOLOGY — For the purposes of this topic, ill appearance in a young infant refers to abnormalities in one or more components of the pediatric assessment triangle (see "Initial assessment and stabilization of children with respiratory or circulatory compromise", section on 'Pediatric assessment triangle'):

●Appearance (any one of the following):

•Decreased muscle tone (limp or weak)

•Difficult to arouse (lethargic)

•Inconsolable crying

•Weak cry

•Unfocused staring (does not fix or follow) in infants ≥8 weeks of age

●Breathing:

•Decreased respiratory effort/apnea

or

•Respiratory distress indicated by:

-Nasal flaring

-Intercostal, subcostal, or suprasternal retractions

-Head bobbing (extension of the head on inhalation and forward movement on exhalation)

-Grunting (harsh, medium-pitched, end-expiratory sound that occurs as the result of exhalation against a partially closed glottis)

-Abdominal breathing (use of abdominal muscles to assist the downward pull of the diaphragm)

●Circulatory status (any one of the following):

•Prolonged capillary refill time (>2 seconds)

•Pallor

•Mottling

•Cyanosis

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.

The interventions commonly needed in critically ill young infants include (see "Pediatric advanced life support (PALS)", section on 'Assessment'):

●Airway:

•For infants who are breathing spontaneously, provide supplemental oxygen to avoid hypoxemia and open the airway as needed with basic airway maneuvers (eg, positioning, head tilt/chin lift, jaw thrust, or insertions of artificial airways). Maintain cervical spine immobilization if concerned about significant head and neck injury. (See "Basic airway management in children", section on 'Noninvasive relief of obstruction'.)

•Because young infants are obligate nasal breathers, ensure that the nares are clear of secretions using gentle nasal suction, as needed.

•Secure airway by rapid sequence intubation in patients who are apneic or at risk for aspiration due to absent gag reflex or altered mental status (eg, lethargy, coma, or prolonged status epilepticus) (table 1). (See "Rapid sequence intubation (RSI) in children for emergency medicine: Approach", section on 'Indications'.)

●Breathing:

•Support breathing, as needed, with bag-valve mask ventilation initially and determine need for additional measures such as:

-High flow oxygen by nasal cannula (table 2) (see "High-flow nasal cannula oxygen therapy in children", section on 'Indications')

-Noninvasive ventilation (see "Noninvasive ventilation for acute and impending respiratory failure in children", section on 'Indications')

-Endotracheal intubation with mechanical ventilation (see "Initiating mechanical ventilation in children")

●Circulation:

•Establish vascular or intraosseous access and obtain initial blood studies (see 'Ancillary studies for infectious etiologies' below and 'Targeted Evaluation' below)

•Identify and treat tachy- or bradyarrhythmias (algorithm 1 and algorithm 2).

•In patients with shock, give an initial rapid infusion of isotonic crystalloid solutions (eg, normal saline or Ringer's lactate); the volume and speed of infusion is determined by the suspected underlying cause and degree of shock and setting as discussed in detail separately. (See "Shock in children in resource-abundant settings: Initial management", section on 'Volume and rate'.)

●Disability:

•Altered mental status (eg, lethargy or coma):

-Obtain a rapid blood glucose and treat hypoglycemia as needed (described for infants >28 days in the table (table 3) and discussed in detail separately for neonates). (See "Approach to hypoglycemia in infants and children", section on 'Immediate management' and "Management and outcome of neonatal hypoglycemia", section on 'Management approach'.)

•Actively seizing: Obtain rapid blood glucose, point-of-care electrolyte studies, and blood and urine studies to evaluate for suspected inborn errors of metabolism (IEM). (See 'Seizures' below.)

-Administer anticonvulsants (eg, midazolam or lorazepam [phenobarbital if neonatal seizures]). (See "Management of convulsive status epilepticus in children", section on 'Emergency antiseizure treatment' and "Treatment of neonatal seizures".)

•Treat underlying causes if present:

-Hypoglycemia (see "Approach to hypoglycemia in infants and children", section on 'Immediate management')

-Hyponatremia (see "Hyponatremia in children: Evaluation and management", section on 'Initial therapy')

-Hypocalcemia (see "Neonatal hypocalcemia", section on 'Management')

-Pyridoxine deficiency, or IEM (see "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management")

●Exposure:

•Treat hypothermia with rewarming. (See "Hypothermia in children: Management", section on 'Rewarming'.)

•Provide active external rewarming (eg, heat lamp) to prevent hypothermia in infants with normal body temperature.

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.

Presumed sepsis

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). Suggested regimens based upon age are provided in the table (table 4). (See "The febrile infant (29 to 90 days of age): Management", section on 'Management' and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial 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 [1] (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

●Pneumonitis

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.

Suspected congenital heart disease — 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 5), 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 [2]. (See "Clinical manifestations and diagnosis of patent ductus arteriosus (PDA) 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 'Cyanosis' below and "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 coarctation of the aorta (see "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Blood pressure and pulses')

However, cardiac disease that requires the ductus for systemic flow can also present with shock or hypotension without a significant upper/lower extremity blood pressure differences (eg hypoplastic left heart). 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'.)

Suspected congenital adrenal hyperplasia — 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 (see "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Management in neonates'):

●Shock

●Hypoglycemia

●Hyponatremia

●Hyperkalemia

Patients with these findings must promptly receive treatment for hypoglycemia, normal saline fluid boluses for shock, and stress doses of hydrocortisone (table 6). 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 and is provided in the table (table 7). (See "Treatment of classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency in infants and children", section on 'Prevention and management of adrenal crisis'.)

Suspected inborn error of metabolism — An acute presentation with multisystem involvement is strongly suggestive of inborn errors of metabolism (IEM). The initial clinical manifestations of acute metabolic decompensation can include (see "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management"):

●Vomiting and anorexia or failure to feed with severe dehydration

●Lethargy that can progress to coma

●Seizures

●Rapid, deep breathing that can progress to apnea

●Hypothermia (related to illness [eg, sepsis], not specific to a particular metabolic pathway)

●Hypoglycemia

●Lactic or severe metabolic acidosis

●Hyperammonemia (may cause respiratory alkalosis)

Pending confirmation of the diagnosis, supportive interventions are undertaken. These include:

●Ventilatory support and fluid resuscitation

●Cessation of all oral intake of breast milk and/or formula

●Continuous dextrose infusion to prevent catabolism and promote anabolism

●Removal of accumulating metabolites (eg, sodium phenylacetate or sodium benzoate administration to patients with hyperammonemia caused by urea cycle defects)

In addition, selected cofactors may be administered, if indicated, before confirmation of the diagnosis and in some cases to support the diagnosis (eg, pyridoxine).

Specific recommendations by suspected metabolic disorder are provided separately. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Immediate management'.)

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, irritability/crying, vomiting, poor feeding, apnea, or limpness). There is typically no clear history or an inconsistent history of trauma (table 8). (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 9). (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), structural brain anomalies, and inborn errors of metabolism (IEM).

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 10). Electroencephalogram is diagnostic in many patients. (See "Etiology and prognosis of neonatal seizures".)

Specific signs and symptoms — The following complaints are often associated with specific conditions (table 11):

●Fever (rectal temperature ≥38°C (100.4°F) points to a bacterial or viral infection but may also occur in patients with intracranial bleeding caused by abusive head trauma or neonatal hemorrhagic stroke. (See "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Child abuse' and "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Infection' and "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Surgical conditions'.)

●HSV infection must be considered for an ill-appearing neonate with 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 congestive heart failure.

●Cyanosis, tachypnea and/or diaphoresis with feeding are frequently seen in infants with congenital heart disease.

●Decreased feeding associated with a poor suck, progressive weakness, poor muscle tone, loss of milestones, and decreased stooling supports the diagnosis of infant botulism. (See "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Bacterial'.)

●Infants who develop nonbilious 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], congenital intestinal atresia), or bowel perforation caused by neonatal appendicitis or necrotizing enterocolitis. (See "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Surgical conditions'.)

●Abdominal distension with infrequent or no stooling suggests bowel obstruction due to anatomic 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 (with a concern for nonaccidental trauma).

●A failure to pass meconium within the first 48 hours of life raises the concern for congenital aganglionic megacolon (HD).

●The urine of some infants with IEM may have an unusual odor (table 12). (See "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Inborn errors of metabolism'.)

Other history — Important features of the perinatal history include the following:

●Maternal infections, fever, and prenatal Group B streptococcal screening and results

●Mode of delivery

●Use of intrapartum antibiotics

●Length of membrane rupture prior to delivery

●Prematurity

●Birth asphyxia

●Need for neonatal intensive care (in particular receiving antibiotics)

●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 "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Causes of acute metabolic decompensation' and "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Inborn errors of metabolism'.)

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 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, decreased activity, respiratory distress, apnea, or signs of circulatory compromise (eg, cool skin, prolonged capillary refill, and mottling). A careful physical examination may identify a combination or pattern of clinical features that suggest the etiology of an infant's symptoms (table 13).

●Vital signs – Important features of vital signs include:

•Fever points to an infectious cause, although lack of fever does not exclude an infectious illness. Hyperthermia may also occur in infants with intracranial hemorrhage due to abusive head trauma/hemorrhagic neonatal stroke, hypernatremia, or with bowel perforation from surgical conditions. (See "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Infection'.)

•Rectal temperature <36.5°C (97.7°F) may occur with sepsis or hypoglycemia [3]. Infants are also more prone to more profound 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 compared with upper suggest 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 "Clinical features and diagnosis of supraventricular tachycardia (SVT) in children", 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 or stroke). Increased head circumference (eg, >85^th percentile for age (figure 1 and figure 2)) 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, respectively) or heart failure.

●Cardiovascular examination – Features of the cardiovascular examination may suggest a congenital defect. Findings to note include (see "Identifying newborns with critical congenital heart disease", section on 'Physical examination'):

•Blood pressure gradient between the arms and legs

•Weak or absent femoral pulses when compared with 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 14)

•The presence of a pathologic heart murmur (table 14), which suggests cardiac disease, although the absence of a murmur does not exclude it

•A gallop rhythm (presence of a third heart sound), 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.

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 (CAH).

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 "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Surgical conditions'.)

●Musculoskeletal examination – An immobile extremity that is painful on passive motion suggests a fracture or, in infants with a fever, 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 bacterial infection, such as pustules, cellulitis, or abscess formation

•Signs of viral infection, such as vesicles (eg, clustered, umbilicated vesicles on an erythematous base consistent with herpes simplex virus)

•Jaundice, which may accompany sepsis or acute bilirubin encephalopathy

•Acrocyanosis (which can sometimes be a nonpathologic finding) or mottling from poor perfusion

•Any bruising in a premobile 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)

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 gas (arterial or venous).

●Blood culture.

●Urinalysis and urine culture (obtained by urethral catheterization).

●Complete blood count with differential.

●Serum electrolytes.

●Ionized calcium.

●Serum lactate.

●Blood urea nitrogen.

●Serum creatinine.

●Serum total bilirubin and alanine and aspartate aminotransferase (ALT/AST).

●C-reactive protein (CRP) and/or procalcitonin.

●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 risk factors and clinical findings, studies to identify viral meningitis (eg, herpes simplex virus or enterovirus). (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Detection of HSV' and "Viral meningitis in children: Clinical features and diagnosis", section on 'Cerebrospinal fluid studies'.)

Lumbar puncture 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 lumbar puncture is deferred.

●For patients with signs of septic shock such as altered mental status, poor perfusion, or hypotension (see "Sepsis in children: Definitions, epidemiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations' and "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)", section on 'Rapid recognition'):

•Prothrombin time (PT), partial thromboplastin time (aPTT), international normalized ratio (INR)

•Fibrinogen and D-dimer

●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

•HSV polymerase chain reaction (PCR) testing of blood and CSF

•Serum ALT and 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 ill-appearing 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 11 and table 13).

In many other patients, confirmation of an alternative diagnosis takes time, and obtaining laboratory studies for sepsis is performed presumptively. (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, viral pneumonitis, congenital heart disease, or pulmonary edema from heart failure. (See 'Abnormal blood chemistries' below.)

Abnormal cardiovascular examination — Patients with an abnormal cardiovascular examination should undergo electrocardiogram (ECG), chest radiograph, four extremity blood pressures, and, for patients who also have cyanosis, the hyperoxia test. (See 'Cyanosis' below.)

These studies frequently can identify specific congenital heart lesions (table 14). They also can provide supportive evidence for the presence of supraventricular tachycardia or other arrhythmias, myocarditis, pericarditis, or anomalous coronary arteries. Consultation with a pediatric cardiologists and echocardiogram (ECHO) provides confirmation of structural cardiac anomalies.

Cyanosis — For infants with cyanosis, assessing the response to 100 percent oxygen can help to distinguish cardiac from pulmonary disease. Oxygen saturation should improve by at least 10 percent for pulmonary causes of cyanosis. An abnormal or equivocal response suggests cardiac disease and warrants further evaluation with echocardiography. (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 more sudden onset of cyanosis at some point after birth 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 – Infants with suspected congenital cyanotic heart disease warrant the following studies (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')f:

•Electrocardiogram (ECG) – ECG findings may suggest a specific anatomic lesion (table 14). A myocardial ischemia pattern may identify infants who have aberrant coronary arteries.

•Chest radiograph – Key findings include cardiomegaly, abnormal heart shape, increased or decreased pulmonary blood flow, or pulmonary edema (table 14).

•Echocardiogram (ECHO) – An ECHO provides the definitive diagnosis for infants with congenital heart disease and is an emergency study in critically ill infants.

●Methemoglobinemia – Patients with methemoglobinemia may appear cyanotic or dusky but have normal or near-normal oxygen saturations as measured by pulse oximetry. (See "Methemoglobinemia".)

•Blood from patients with methemoglobinemia is dark red, chocolate, or brownish to blue in color and does not change when exposed to oxygen (picture 2).

•Methemoglobinemia is strongly suggested when there is clinical cyanosis in the presence of a calculated normal arterial pO₂ (P_aO₂) 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 (IEM) based upon degree of suspicion as shown in the table (table 15)

●Blood ethanol level if intentional poisoning is suspected

●Rapid urine screen for drugs of abuse if either intentional poisoning or secondary exposure to maternal drugs of abuse 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 IEM and may be associated with sudden decompensation with diet change or marked metabolic acidosis, hyperammonemia with respiratory alkalosis, urinary ketones or hypoglycemia (table 16). Further evaluation for IEM depends upon the presenting features as shown in the table (table 15). (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management" 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 infections (diarrhea is frequently also present), urinary tract infections, conditions causing respiratory distress, increased intracranial pressure, and IEM.

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 obstruction, perforation, or other abnormalities [4] such as:

●Necrotizing enterocolitis – Findings of necrotizing enterocolitis include pneumatosis intestinalis (gas within the intestinal wall), portal venous gas, or pneumoperitoneum (image 1). (See "Neonatal necrotizing enterocolitis: Clinical features and diagnosis".)

●Malrotation or pyloric stenosis – With malrotation or pyloric stenosis, there may be duodenal or gastric distention with a paucity of air distally. (See "Intestinal malrotation in children", section on 'Clinical presentation' and "Infantile hypertrophic pyloric stenosis", section on 'Clinical manifestations'.)

Hemodynamically stable young infants with bilious emesis but no sign of gastrointestinal perforation on plain radiographs should undergo immediate upper gastrointestinal (UGI) contrast studies with small bowel follow through. A duodenal bulb that overlies the spine and/or a medially directed cecum suggests malrotation (image 2 and image 3). A corkscrew appearance in the small bowel can be seen with volvulus (image 4). (See "Intestinal malrotation in children", section on 'Diagnosis'.)

An abdominal ultrasound is the preferred study to detect pyloric stenosis suggested by projectile nonbilious vomiting (image 5).

●Hirschsprung disease – Hirschsprung disease (HD) may present with megacolon, enterocolitis, or signs of large bowel obstruction. (See "Congenital aganglionic megacolon (Hirschsprung disease)", section on 'Clinical presentation'.)

Contrast enema helps support the diagnosis of HD (image 6) and confirms the diagnosis of meconium ileus (image 7). (See "Congenital aganglionic megacolon (Hirschsprung disease)", section on 'Diagnosis' and "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Meconium ileus'.)

●Cystic fibrosis – Cystic fibrosis may demonstrate a meconium ileus (image 8). (See "Cystic fibrosis: Overview of gastrointestinal disease", section on 'Meconium ileus'.)

●Bowel perforation – Patients with perforation noted on plain abdominal radiographs require emergency consultation and further management guided by a pediatric surgeon.

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 17). (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 (as well as oral injuries, nose/mouth bleeds, and subconjunctival hemorrhages outside of the delivery period) 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 18 and table 19). 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 jaundice caused by unconjugated hyperbilirubinemia in children", section on 'Diagnostic approach' and "Unconjugated hyperbilirubinemia in term and late preterm newborns: Screening", section on 'Approach to screening'.)

Ill infants who have high unconjugated (indirect) hyperbilirubinemia may have acute bilirubin encephalopathy (calculator 1). (See "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Acute bilirubin encephalopathy (kernicterus)'.)

Conjugated hyperbilirubinemia suggests, IEM, 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 cerebrospinal fluid (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 20). (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Interpretation' 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), congenital pulmonary malformations, mediastinal masses, 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 'Rapidly available tests'.)

Urosepsis may be associated with galactosemia or posterior urethral valves (although most cases are not secondary to these diagnoses). 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'.)

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 3). Severe hypoglycemia is also associated with shock, congenital adrenal hyperplasia (CAH), and IEM. (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 21)

•IEM

•Congenital heart disease

•Methemoglobinemia

•Carbon monoxide poisoning

•Necrotizing enterocolitis

•Any surgical condition resulting in perforation or bowel ischemia

●Infants with pyloric stenosis may develop hypochloremic, hypokalemic metabolic alkalosis from loss of gastric hydrochloric acid as the result of persistent vomiting and loss of potassium in the urine as the kidneys reabsorb water in response to dehydration. However, the absence of these metabolic derangements does not exclude the diagnosis. (See "Infantile hypertrophic pyloric stenosis", section on 'Later presentation (classic)'.)

●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 "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Hyponatremia'.)

●Hypernatremia typically occurs as the result of sodium (salt) poisoning, excessive loss of free water (as can occur with arginine vasopressin deficiency or resistance [previously called central or nephrogenic diabetes insipidus, respectively]), or loss of water in excess of sodium losses. (See "Fluid and electrolyte therapy in newborns", section on 'Hypernatremia' and "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Hyponatremia'.)

●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, vitamin D deficiency leading to rickets, and renal or hepatic dysfunction. (See "Etiology of hypocalcemia in infants and children".)

●Hyperammonemia is a characteristic finding in urea cycle defects and can sometimes occur in organic acidemias, fatty acid oxidation defects, and liver dysfunction. (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Hyperammonemia'.)

SUMMARY AND RECOMMENDATIONS

●Terminology – Ill appearance in a young infant refers to abnormalities in one or more components of the pediatric assessment triangle (appearance, circulation, and breathing). (See 'Terminology' above and "Initial assessment and stabilization of children with respiratory or circulatory compromise", section on 'Pediatric assessment triangle'.)

●Stabilization and empiric therapy – 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):

•Antimicrobial therapy (most patients) – 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 4). (See "The febrile infant (29 to 90 days of age): Management", section on 'Ill-appearing' and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Neonates 8 to 21 days old' and "The febrile neonate (28 days of age or younger): Outpatient evaluation and initial management", section on 'Ill-appearing'.)

Neonates (infants younger than 28 days of age) who have mucocutaneous vesicles, seizures, CSF pleocytosis with a negative Gram stain, shock/severe ill-appearance, 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 'Initial antiviral therapy'.)

•Patients with signs of ductal-dependent congenital heart disease – For hypoxic, hemodynamically unstable infants with ductal-dependent congenital heart disease (table 5), treatment with prostaglandin E1 (PGE1, alprostadil) to reopen the ductus arteriosus (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 'Suspected congenital heart disease' above and "Diagnosis and initial management of cyanotic heart disease in the newborn", section on 'Prostaglandin E1'.)

•Patients with suspected adrenal crisis – 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 6). Whenever possible, a blood sample for steroid hormone measurements (most importantly, 17-hydroxyprogesterone) should be obtained prior to hydrocortisone administration. (See 'Suspected congenital adrenal hyperplasia' above and "Treatment of adrenal insufficiency in children", section on 'Adrenal crisis'.)

•Patients with suspected inborn errors of metabolism (IEM) – For infants with suspected IEM and pending confirmation of the diagnosis, supportive interventions include provision of ventilatory support and fluid resuscitation, discontinuation of oral feeds, removal of accumulating metabolites, and prevention of catabolism (by promoting anabolism, typically with a dextrose infusion). In addition, selected cofactors may be administered, if indicated, before confirmation of the diagnosis and in some cases to support the diagnosis (eg, pyridoxine). (See "Metabolic emergencies in suspected inborn errors of metabolism: Presentation, evaluation, and management", section on 'Immediate management'.)

●Differential diagnosis – Ill-appearing young infants often have an infectious cause. However, the physician should carefully evaluate for other important conditions (table 22). (See "Ill-appearing infant (younger than 90 days of age): Causes", section on 'Differential diagnosis'.)

●Evaluation – Historical features, physical findings, and initial ancillary studies may provide clues to a specific diagnosis (table 11 and table 13). (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.)