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INFANT FORMULAS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Infant formulas are the primary source of nutrition for the non-breast fed infant. Enteral formulas intended for adults are not discussed in this management.

Specific Substances

    1) Alimentum
    2) Alsoy
    3) Carnation Follow-Up Formula
    4) Carnation Good Start
    5) Enfamil
    6) Enfamil Human Milk Fortifier
    7) Enfamil with Iron
    8) Enfamil Premature Formula
    9) Enfamil Premature Formula with Iron
    10) Gerber Baby Formula with Iron
    11) Gerber Soy Formula
    12) Isomil
    13) Isomil SF
    14) Lactofree
    15) Nursoy
    16) Nutramigen
    17) Preemie SMA 20
    18) Preemie SMA 24
    19) Pregestimil
    20) ProSobee
    21) RCF
    22) Similac 13
    23) Similac 20
    24) Similac 24
    25) Similac 27
    26) Similac with Iron 20
    27) Similac Natural Care Human Milk Fortifier
    28) Similac PM 60/40
    29) Similac Special Care 20
    30) Similac Special Care 24
    31) Similac Special Care with Iron 24
    32) SMA 13
    33) SMA 20
    34) SMA 24
    35) SMA 27
    36) SMA Lo-Iron 13
    37) SMA Lo-Iron 20
    38) SMA Lo-Iron 24
    39) Soyalac
    40) FORMULA (INFANT)

Available Forms Sources

    A) FORMS
    1) ERRORS IN DILUTION: Of infant formulas are not uncommon. In a study of 133 mothers who brought in prepared formula for analysis, 6% were hypoconcentrated and 5% were hyperconcentrated.
    a) Formulas were considered abnormally concentrated if an error of 35% or greater in the amount of water added was detected.
    b) Mothers using hypoconcentrated formula were primarily in a low-income group, while those using hyperconcentrated formula had a tendency toward infants who were underweight (McJunkin et al, 1987).
    2) ERRORS IN CONCENTRATION: Of formula may also occur inadvertently as a result of incorrect filling of the scoop by using heaped instead of level scoops, with powdered formula (Chambers & Steel, 1975; Taitz & Beyers, 1972) or mistaking the liquid concentrate for ready-to-feed formula (Nelson & Catterton, 1985).
    3) ALUMINUM CONTENT OF INFANT FORMULAS (Koo et al, 1988)
    PRODUCTALUMINUM (mcg/L)
    Enfamil17-349
    Enfamil Premature298-846
    Isomil603-1084
    Isomil SF910-1460
    Lofenalac348-562
    Nursoy557-1840
    Nutramigen1126-1594
    Prosobee684-2346
    Pregestimil725-732
    Similac14-353
    Similac LBW292-386
    SMA15-250
    Soyalac455

    B) SOURCES
    1) SALMONELLA INFECTION - At least 6 outbreaks of Salmonella infection in infants (n=287) linked to powdered infant formula have been reported. In many cases, it was difficult to detect salmonellae in routine quality-control sampling because of the low level of salmonellae (eg, 1.6 organisms per 450 g) in the infant formulas (Cahill et al, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Infant formulas are the primary source of nutrition for the non-breast fed infant. Enteral formulas intended for adults are not discussed in this management.
    B) TOXICOLOGY: Improperly reconstituted infant (OVERCONCENTRATED) formula: Hypernatremia has a multifactorial etiology: (1) increased obligatory urinary free water losses because of increased renal solute load; (2) reduced formula ingestion because of poor palatability of the formula; (3) increased gastrointestinal losses from an osmotic diarrhea; (4) increased insensible losses from fever because of an intercurrent illness; and (5) increased sodium retention from the modestly elevated sodium concentration in the feeds.
    C) EPIDEMIOLOGY: Errors in dilution of infant formulas are not uncommon. In one study, 6% of infant formulas were underconcentrated and 5% were overconcentrated. Formulas were considered abnormally concentrated if an error of 35% or greater in the amount of water added was detected.
    D) WITH POISONING/EXPOSURE
    1) OVERCONCENTRATED FORMULA: Administration of the concentrated formula in place of prepared or ready-to-feed formula has resulted in hypernatremia, lethargy, hypotonia, diarrhea, vomiting, metabolic acidosis, and dehydration. Concentrated formula is hyperosmolar and has also been associated with necrotizing enterocolitis in infants.
    2) UNDERCONCENTRATED FORMULA: Water intoxication due to excessive free water intake from dilute formula or additional water has resulted in hyponatremia, hypothermia, seizures, respiratory distress, and pulmonary edema.
    3) ADULTERATED FORMULA: There are sporadic reports of inadvertent or deliberate adulteration of infant formulas with other household products such as boric acid or baking soda. In children with signs or symptoms of intoxication related to formula ingestion, adulterants should be considered. The addition of oral medications to infant formula, such as calcium glubionate, phenobarbital, or dexamethasone, may result in a hyperosmolar solution, and has been associated with the development of necrotizing enterocolitis in neonates.
    4) SALMONELLA INFECTION: At least 6 outbreaks of Salmonella infection (n=287 cases) have been linked to powdered infant formulas.
    5) ALUMINUM TOXICITY: Infants with congenital uremia are at risk for developing aluminum toxicity. Proprietary infant formula was the primary source of aluminum in two infants.
    6) INADVERTENT INTRAVENOUS ADMINISTRATION: Inadvertent intravenous administration of infant formula has resulted in hypotension, bradycardia, metabolic acidosis, seizures, respiratory arrest, fever, and DIC.

Laboratory Monitoring

    A) If formula misuse is suspected (ie over or under dilution), monitor fluid status, acid-base status, plasma osmolality, serum electrolytes (especially sodium), urine output and urine electrolytes.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) HYPERNATREMIC DEHYDRATION: The first priority is replacement of the intravascular volume with isotonic saline.
    2) HYPERVOLEMIC HYPONATREMIA: Treatment is mainly sodium and water restriction.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) HYPERNATREMIC DEHYDRATION: Replace the intravascular volume with isotonic saline. In moderately to severely dehydrated patients, restoration of intravascular volume should take place over 30 to 45 minutes with normal saline or lactated Ringer's solution (dose, 20 mL/kg IV, followed by a bolus of 10 mL/kg if response is poor). Once the intravascular volume is restored, the water deficit may be replaced with D5W and 0.2% NS. Maintenance fluids must also be given. The final administered solution should contain 20 to 40 mEq/L of sodium. The rate of administration should be slow. A decrease in osmolality of 2 mosmol/hr (1 mEq/L/hr sodium) appears to be an acceptable rate for lowering tonicity. Serum sodium should be corrected slowly over 48 to 72 hours.
    2) HYPERVOLEMIC HYPONATREMIA: Treatment is mainly sodium and water restriction. For more severe cases, diuretic therapy can be used to excrete water in excess of sodium. Calculate water excess and determine how much negative water balance to maintain per day. Measure urine osmolality and urine electrolytes daily to recalculate actual loss. Fluid excess should be corrected gradually over 4 to 6 days.
    3) SEIZURES: Seizures in the setting of formula misuse are most commonly secondary to hyponatremia from feeding infants free water or overly dilute formula. Monitor and correct electrolyte imbalances. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur.
    C) DECONTAMINATION
    1) Toxicity generally develops over hours to days from electrolyte imbalances. Gastrointestinal decontamination is NOT recommended. DILUTION: Infants or children who have been receiving overly concentrated formula and are alert and tolerating fluids may benefit from dilution. Immediately dilute with 4 to 8 ounces of water, NOT to exceed 15 mL/kg.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be necessary if coma or recurrent seizures secondary to hyponatremia develop.
    E) ANTIDOTE
    1) No antidote is available.
    F) ENHANCED ELIMINATION
    1) Excessive sodium absorbed will be renally eliminated. Enhanced elimination is generally unnecessary except in patients with renal failure and severe hypernatremia or volume overload.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients or those with mild diarrhea can be managed at home.
    2) OBSERVATION CRITERIA: Patients with deliberate overdose or severe diarrhea should be referred to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients with significant hypernatremia, confusion, dehydration, or hypotension should be admitted, observed, and carefully rehydrated. All symptomatic patients with a serum sodium level greater than 155 milliequivalents/liter who require intravenous fluid therapy should be admitted. All symptomatic patients with a serum sodium level less than 130 milliequivalents/liter should be admitted. Patients with levels less than 120 milliequivalents/liter should be admitted to an intensive care unit until the deficit is corrected.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity. Severe toxicity is exceedingly rare.
    H) PITFALLS
    1) Missing an ingestion of another chemical or other possible etiologies for a patient’s symptoms. Consider child abuse or Munchausen syndrome by proxy. History of exposure may be difficult to obtain in some settings.
    I) DIFFERENTIAL DIAGNOSIS
    1) Dehydration may develop from multiple causes (eg, gastroenteritis).

Range Of Toxicity

    A) TOXICOLOGY: Toxic effects primarily occur in infants receiving overconcentrated, underconcentrated, or adulterated formulas, and are not related to the total amount of formula.

Clinical Effects

Summary Of Exposure

    A) USES: Infant formulas are the primary source of nutrition for the non-breast fed infant. Enteral formulas intended for adults are not discussed in this management.
    B) TOXICOLOGY: Improperly reconstituted infant (OVERCONCENTRATED) formula: Hypernatremia has a multifactorial etiology: (1) increased obligatory urinary free water losses because of increased renal solute load; (2) reduced formula ingestion because of poor palatability of the formula; (3) increased gastrointestinal losses from an osmotic diarrhea; (4) increased insensible losses from fever because of an intercurrent illness; and (5) increased sodium retention from the modestly elevated sodium concentration in the feeds.
    C) EPIDEMIOLOGY: Errors in dilution of infant formulas are not uncommon. In one study, 6% of infant formulas were underconcentrated and 5% were overconcentrated. Formulas were considered abnormally concentrated if an error of 35% or greater in the amount of water added was detected.
    D) WITH POISONING/EXPOSURE
    1) OVERCONCENTRATED FORMULA: Administration of the concentrated formula in place of prepared or ready-to-feed formula has resulted in hypernatremia, lethargy, hypotonia, diarrhea, vomiting, metabolic acidosis, and dehydration. Concentrated formula is hyperosmolar and has also been associated with necrotizing enterocolitis in infants.
    2) UNDERCONCENTRATED FORMULA: Water intoxication due to excessive free water intake from dilute formula or additional water has resulted in hyponatremia, hypothermia, seizures, respiratory distress, and pulmonary edema.
    3) ADULTERATED FORMULA: There are sporadic reports of inadvertent or deliberate adulteration of infant formulas with other household products such as boric acid or baking soda. In children with signs or symptoms of intoxication related to formula ingestion, adulterants should be considered. The addition of oral medications to infant formula, such as calcium glubionate, phenobarbital, or dexamethasone, may result in a hyperosmolar solution, and has been associated with the development of necrotizing enterocolitis in neonates.
    4) SALMONELLA INFECTION: At least 6 outbreaks of Salmonella infection (n=287 cases) have been linked to powdered infant formulas.
    5) ALUMINUM TOXICITY: Infants with congenital uremia are at risk for developing aluminum toxicity. Proprietary infant formula was the primary source of aluminum in two infants.
    6) INADVERTENT INTRAVENOUS ADMINISTRATION: Inadvertent intravenous administration of infant formula has resulted in hypotension, bradycardia, metabolic acidosis, seizures, respiratory arrest, fever, and DIC.

Vital Signs

    3.3.3) TEMPERATURE
    A) HYPOTHERMIA was a common finding in a series of infants with water intoxication, many from ingestion of overly diluted milk or formula (Medani, 1987; Partridge et al, 1981).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) GANGRENOUS DISORDER
    1) Gangrene was seen as a complication of ingesting over concentrated milk formula (Abrams et al, 1975).
    B) HYPOTENSIVE EPISODE
    1) Villalobos et al (1995) described 2 patients who inadvertently received infant formula intravenously. An 11-month-old received 10 mL Isomil IV and developed immediate bradycardia and respiratory arrest. She required intensive care for 2 weeks because of complications (seizures, hypotension, DIC, metabolic acidosis). A 17-month-old received 40 mL Pregestimil IV and developed fever (41 C), hypotension and hypoxia. She required vasopressors for 12 hours and ventilatory support for 2 days (Villalobos et al, 1995).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) Infants with water intoxication due to excessive dilution of formula may have pulmonary edema (Medani, 1987).
    2) Intubation was required in several of these infants due to respiratory distress (Medani, 1987).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) Hypotonia and lethargy were observed in one of 5 infants who were fed overconcentrated formula. The serum sodium in this infant was 176 mEq/L (Birenbaum et al, 1981).
    B) SEIZURE
    1) Overdilution of formula, resulting in excessive free water intake, has caused signs and symptoms of water intoxication, including seizures, somnolence, irritability, and hyponatremia (Grant et al, 1994; Medani, 1987).
    2) CASE REPORT: Seizures secondary to hyponatremia (Na 107 mmol/L) were reported in a 6-month-old who had been given non-dairy coffee creamer (Cremora(R)) 2 teaspoons per 8 ounce bottle as a milk/formula substitute (Hendrickson, 2000).
    C) TETANY
    1) Administration of a high-phosphate infant formula was associated with the development of neonatal tetany (Gardner, 1986).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) ENTEROCOLITIS
    1) CASE REPORT: Inadvertent feeding of concentrated liquid formula in place of ready-to-feed liquid was associated with fatal necrotizing enterocolitis (NEC) in a newborn (Nelson & Catterton, 1985).
    2) CASE REPORT: NEC was also documented in a 12-day-old infant who presented with dehydration due to inadequate breast milk intake following slow oral rehydration with infant formula. This infant had other predisposing factors for NEC, polycythemia and hypoglycemia (Clarke & Sibert, 1985).
    B) INTESTINAL OBSTRUCTION
    1) CASE SERIES: Administration of formula supplemented with a calcium-phosphate mixture was associated with complete ileal obstruction due to formation of insoluble soaps from calcium and long-chain fatty acids in 3 premature low-birth-weight infants (Koletzko et al, 1988).
    2) CASE SERIES: Intestinal obstruction was described in 3 premature infants fed powdered milk formula. Two cases resolved with conservative therapy and one case was initially treated with Gastrografin and saline enemas. Surgery was ultimately required (Cremin et al, 1970).
    C) DIARRHEA
    1) Infants fed overconcentrated formula most frequently present with acute diarrhea (Birenbaum et al, 1981).
    D) VOMITING
    1) CASE REPORT: Vomiting was observed in 2 infants who were fed overconcentrated formula (Birenbaum et al, 1981).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) ACIDOSIS
    1) METABOLIC ACIDOSIS: Severe metabolic acidosis was noted in a dehydrated infant who had been given concentrated formula (Nelson & Catterton, 1985).
    B) ALKALOSIS
    1) METABOLIC ALKALOSIS: Hypochloremic metabolic alkalosis has been reported in children exposed to formulas deficient in chloride (Kaleita, 1986).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DISSEMINATED INTRAVASCULAR COAGULATION
    1) CASE REPORT: Disseminated intravascular coagulation occurred as a complication in an infant with severe hypertonic dehydration (Abrams et al, 1975).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) CASE REPORT: Hyperglycemia developed in a 7-week-old infant fed overconcentrated milk formula (Abrams et al, 1975).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) A 7-week-old boy with a history of eczema and suspected allergy to cow's milk and soy formula was switched to a partially hydrolyzed whey formula. He developed some vomiting after the first feeding, then wheezing. After the second feeding he developed diarrhea, labored breathing that progressed to severe wheezing and respiratory distress. He presented to a pediatrician in cardiac arrest, was successfully resuscitated but died 21 hours after admission to the hospital. Autopsy was consistent with anaphylaxis and RAST testing detected IgE antibodies against milk, wheat and soybean proteins (Tarim et al, 1994).
    3.19.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) ANAPHYLACTOID REACTION
    a) GUINEA PIG: In a guinea pig model, various formulas were tested for anaphylactic sensitizing properties. Cow milk had a high degree of sensitizing capability, soy formula was less sensitizing, and casein hydrolysate and cow collagen soy protein hydrolysate were not sensitizing (Piacentini et al, 1991).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) If formula misuse is suspected (ie over or under dilution), monitor fluid status, acid-base status, plasma osmolality, serum electrolytes (especially sodium), urine output and urine electrolytes.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Symptoms related to formula misuse involve fluid and electrolyte imbalance. Monitor fluid status, acid-base status, plasma osmolality, and serum electrolytes, especially sodium, as indicated.
    B) ACID/BASE
    1) Monitor acid-base status in cases of formula misuse.
    4.1.3) URINE
    A) OTHER
    1) Monitor urine electrolytes, specific gravity, and output in symptomatic infants.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant hypernatremia, confusion, dehydration, or hypotension should be admitted, observed, and carefully rehydrated.
    B) All symptomatic patients with a serum sodium level greater than 155 milliequivalents/liter who require intravenous fluid therapy should be admitted.
    C) All symptomatic patients with a serum sodium level less than 130 milliequivalents/liter should be admitted. Patients with levels less than 120 milliequivalents/liter should be admitted to an intensive care unit until the deficit is corrected.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients or those with mild diarrhea can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity. Severe toxicity is exceedingly rare.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate overdose or severe diarrhea should be referred to a healthcare facility for evaluation.

Monitoring

    A) If formula misuse is suspected (ie over or under dilution), monitor fluid status, acid-base status, plasma osmolality, serum electrolytes (especially sodium), urine output and urine electrolytes.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Toxicity generally develops over hours to days from electrolyte imbalances. Gastrointestinal decontamination is NOT recommended.
    B) DILUTION
    1) Infants or children who have been receiving overly concentrated formula and are alert and tolerating fluids may benefit from dilution. Immediately dilute with 4 to 8 ounces of water, NOT to exceed 15 mL/kg.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY
    1) Toxicity generally develops over hours to days from electrolyte imbalances. Gastrointestinal decontamination is NOT recommended.
    B) DILUTION
    1) Infants or children who have been receiving overly concentrated formula and are alert and tolerating fluids may benefit from dilution.
    2) Immediately dilute with 4 to 8 ounces of water, NOT to exceed 15 mL/kg.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor fluid status, acid-base status, plasma osmolality, and serum electrolytes, especially sodium, urine output and urine electrolytes as indicated.
    B) HYPERNATREMIA
    1) The first priority is replacement of the intravascular volume with isotonic saline. In moderately to severely dehydrated patients, restoration of intravascular volume should take place over 30 to 45 minutes with normal saline or lactated Ringers solution.
    2) DOSE: 20 mL/kg intravenously. Repeat a bolus of 10 mL/kg if response is poor.
    3) Once the intravascular volume is restored, the water deficit may be replaced with dextrose 5% in water and 0.2% normal saline.
    4) Maintenance fluids must also be given. The final administered solution should contain 20 to 40 mEq/L of sodium. The rate of administration should be slow.
    5) A decrease in osmolality of 2 milliosmoles/hour (1 mEq/L/hour sodium) appears to be an acceptable rate for lowering tonicity.
    6) Serum sodium should be corrected slowly over 48 to 72 hours. If the serum sodium level is greater than 175 milliequivalents/liter, the sodium level should be decreased by 15 milliequivalents/liter/day.
    a) If the sodium level is less than 175 mEq/L, the concentration should be lowered halfway to normal during the first 24 hours.
    C) HYPONATREMIA
    1) Most patients will require sodium and water restriction as they have an excessive amount of both. For more severe cases, diuretic therapy can be used to excrete water in excess of sodium.
    2) Calculate water excess and determine how much negative water balance to maintain per day. Measure urine osmolality and urine electrolytes daily to recalculate actual loss. Fluid excess should be corrected gradually over 4 to 6 days.
    3) In patients with CNS symptoms or sodium level less than 115 mEq/L, furosemide may be given in addition to fluid restriction. DOSE: 1 mg/kg intravenously; may repeat, depending on desired urine output and speed of response.
    D) SEIZURE
    1) Seizures in the setting of formula misuse are most commonly secondary to hyponatremia from feeding infants free water or overly dilute formula. Monitor and correct electrolyte imbalances.
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) Generally, excessive sodium absorption will be renally eliminated. Enhanced elimination is generally unnecessary except in patients with renal failure and severe hypernatremia or volume overload.

Abstracts

Case Reports

    A) INFANT
    1) A newborn girl, weighing 3,429 grams at discharge, was inadvertently given a concentrated liquid formula by her mother. The mother was illiterate and did not realize the difference between the ready-to-feed and concentrated formula.
    2) At 6 days of age, the infant developed persistent vomiting and diarrhea. Upon admission to the hospital at 9 days of age she was dehydrated, with hyperpnea (64/min), hypernatremia (178 mEq/L), hyperkalemia (6.8 mEq/L), hyperchloremia (149 mEq/L), and acidosis (pH 6.94).
    3) Abdominal x-ray revealed necrotizing enterocolitis (NEC). The infant had a cardiac arrest and died 12 hours after admission. Severe NEC was confirmed on autopsy (Nelson & Catterton, 1985).

Range Of Toxicity

Summary

    A) TOXICOLOGY: Toxic effects primarily occur in infants receiving overconcentrated, underconcentrated, or adulterated formulas, and are not related to the total amount of formula.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) This product is not intended for adult use.
    7.2.2) PEDIATRIC
    A) Preparation of infant formula should always be based on the manufacturer's instructions. General guidelines are provided below:
    B) POWDERED FORMULA
    1) Mix 2 ounces (60 mL) of sterile water for every one leveled scoop of dry powder(United States Department of Agriculture, 2009; Abbott Nutrition, 2011; Mead Johnson Nutrition, 2011).
    C) CONCENTRATED FORMULA
    1) Mix equal parts of concentrated liquid formula with sterile water (United States Department of Agriculture, 2009; Abbott Nutrition, 2011).
    D) READY-TO-USE FORMULA
    1) Ready-to-use formula does not require dilution (United States Department of Agriculture, 2009; Abbott Nutrition, 2011).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Toxicity from improper use of infant formulas is generally related to the concentration or osmolality of the preparation, and not to the total volume of formula.
    2) MEASUREMENT ERRORS: Even small errors in concentration may result in adverse consequences. In a series of 3 cases, the use of heaped scoopfuls instead of level scoops resulted in hypernatremic dehydration (Tartz & Byers, 1972) .
    3) In a study comparing osmolality using two different methods of preparation, the formula prepared using heaped scoopfuls had an increased sodium concentration by 15 mEq/L (Colle et al, 1958).
    a) Measurement by scoopful can produce inconsistencies in the amount used to prepare formulae. The highest weight for a scoopful was 5.6 grams, the lowest was 2.8 grams (Jeffs, 1989).
    B) SPECIFIC SUBSTANCE
    1) IRON: Prepared commercial formula contains 8 to 12 milligrams of iron per quart. Premature infants can develop hemolytic anemia from excessive iron intake (8 milligrams/kilogram/day or more).
    a) Excessive iron is not likely to be obtained from formula alone. A 2 kilogram infant ingesting 130 calories/kilogram/day would receive a maximum of 1.6 milligrams/kilogram/day of iron.
    b) The current upper limit is about 3 mg/100 kilocalorie (Dallman, 1989).
    c) One study compared 9-month-old children fed cow's milk, formula with 0.9 milligrams iron/liter, and formula with 12 milligrams iron/liter over 3 months. There was no difference in the incidence of infections, diarrhea, constipation, gastrointestinal problems, general morbidity or weight gain among the groups. Even in populations with a low incidence of iron deficiency, this level of iron supplementation was not associated with adverse effects (Singhal et al, 2000).
    2) VITAMIN E: The potential for toxicity with Vitamin E is uncertain. Some investigators have found increased risk of sepsis, necrotizing enterocolitis, and hemorrhagic complications while others have not substantiated this (Bell , 1989).
    a) A level of 10 mg/100 Kcal (15 international units per 100 kilocalorie) has been recommended (Bell, 1989).
    3) IODINE: The upper limit of iodine proposed by the Food and Drug Administration (1985) is 75 microgram per 100 Kcal per day (Fisher, 1989).
    4) SELENIUM: The recommended maximum amount for infant formulas is 10 to 45 grams/day (Levander, 1989).
    5) LEAD: Water containing high levels of lead has caused elevations of serum lead in an infant whose formula was prepared with the water (Shannon & Graif, 1989).
    6) NITRITES: Infants who are fed formula and other infant foods prepared with contaminated well water are at high risk of developing methemoglobinemia; significant cyanosis in infants can result from ingestion of well water containing as little as 90 ppm of nitrate and death at 150 ppm (Johnson, 1987). Methemoglobinemia has been documented in infants ingesting municipal water containing 13.3 to 24.4 ppm of nitrate-nitrogen (Virgil et al, 1965; Jones et al, 1973).

Pharmacology Toxicology

Toxicologic Mechanism

    A) IMPROPERLY RECONSTITUTED (OVERCONCENTRATED) INFANT FORMULA - Hypernatremia has a multifactorial etiology.
    B) HUMAN
    1) IMPROPERLY RECONSTITUTED INFANT (OVERCONCENTRATED) FORMULA - Hypernatremia has a multifactorial etiology: (1) increased obligatory urinary free water losses because of increased renal solute load; (2) reduced formula ingestion because of poor palatability of the formula; (3) increased gastrointestinal losses from an osmotic diarrhea; (4) increased insensible losses from fever because of an intercurrent illness; and (5) increased sodium retention from the modestly elevated sodium concentration in the feeds (Moritz, 2007).

References

General Bibliography

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