Management of complicated severe acute malnutrition in children in resource-limited settings

INTRODUCTION — Severe acute malnutrition (SAM) is a pervasive problem throughout resource-limited settings [1]. Severely malnourished children are often identified when brought to medical attention for an acute issue, such as diarrhea or fever, but should also be sought through community-wide screenings of vulnerable children in high-risk settings. In some cases, SAM is precipitated by political disruptions like war or natural disasters like drought, which interfere with the food supply. However, more often, SAM is simply a disease of pervasive poverty and poor hygienic conditions, compounded by socioeconomic disparities [2], seasonal shortages of food, and spikes in illnesses such as malaria or infectious diarrhea.

This topic review will discuss treatment of children with complicated SAM (eg, with concomitant dehydration or severe infections). Affected children are treated as inpatients in hospitals or feeding centers, using protocols promoted by the World Health Organization (WHO). In the past, this approach was used for most children with SAM. However, experience over the last 20 years has demonstrated that children with uncomplicated SAM, constituting the vast majority of malnourished children, can and should be treated at home with support from outpatient feeding programs. This community-based management of acute malnutrition (CMAM) approach appears to produce equal or better recovery and case fatality rates, and to widen population coverage, and has been successfully implemented worldwide by governments and relief organizations. As a result, CMAM has become the international standard of care for uncomplicated cases of severe malnutrition [3-5].

Other UpToDate topic reviews with related content are:

●(See "Malnutrition in children in resource-limited settings: Clinical assessment".)

●(See "Management of moderate acute malnutrition in children in resource-limited settings".)

●(See "Management of uncomplicated severe acute malnutrition in children in resource-limited settings".)

●(See "Micronutrient deficiencies associated with protein-energy malnutrition in children".)

The treatment of malnourished children from resource-abundant settings is discussed separately. Although the principles of treatment of malnourished children from resource-abundant settings are similar to those from resource-limited settings, the specific details vary based on local customs and resources. (See "Poor weight gain in children younger than two years in resource-abundant settings: Management".)

CLASSIFICATION BY AGE AND SEVERITY — In 2023, the World Health Organization (WHO) proposed changes in nomenclature, such that severe acute malnutrition (SAM) will be termed "severe wasting and/or nutritional edema" [5,6]. Moderate acute malnutrition (MAM) will be termed "moderate wasting."

Pending widespread adoption of this terminology, we will continue to use the traditional terms SAM and MAM for simplicity and consistency with the historical literature.

Children 6 to 59 months — SAM can occur in people of all ages but has its highest incidence and is best studied in children between 6 and 59 months of age. Therefore, protocols for diagnosis and triage focus on this age group, as outlined in the following sections.

The WHO international growth standards should be used to identify and classify the degree of acute malnutrition in developmentally normal children [7]. These criteria are based on the degree of wasting and the presence of edema, where wasting is identified by measuring mid-upper arm circumference (MUAC) or determining the weight-for-height Z-score (WHZ). Children should be classified based on whichever criterion deviates most from normal; for example, if a child is moderately malnourished by MUAC but severely malnourished by WHZ, the child should be classified as severely malnourished. (See "Malnutrition in children in resource-limited settings: Clinical assessment", section on 'Clinical assessment'.)

The diagnostic criteria for acute malnutrition are (table 1):

●Moderate acute malnutrition (MAM):

•MUAC 11.5 to 12.4 cm (115 to 124 mm), or

•WHZ -2 to -3 (ie, weight-for-length between 2 and 3 standard deviations [SD] below the median)

●Severe acute malnutrition (SAM):

•MUAC <11.5 cm (<115 mm), or

•WHZ <-3 (ie, weight-for-length more than 3 SD below the median), or

•Bilateral pitting edema

Note that the presence of bilateral pitting edema is diagnostic of kwashiorkor (edematous malnutrition); due to the profound physiologic perturbations associated with kwashiorkor, children with any degree of symmetric pitting edema should be considered severely malnourished, regardless of WHZ or MUAC. Such edema begins in the most gravitationally dependent areas of the body and is classified as 1⁺ if in the feet and lower legs only, 2⁺ if it extends to the upper body or arms, or 3⁺ if it extends to the face.

Most children with acute malnutrition also have evidence of stunting (impaired linear growth), which traditionally is considered a marker of chronic malnutrition. This distinction between "acute" and "chronic" malnutrition is useful for clinical management but does not reflect a true physiologic difference and is potentially misleading as the two often coexist. Moderate stunting is defined by height- or length-for-age Z-score between -2 and -3. Management of acute malnutrition is similar regardless of whether there is underlying chronic malnutrition, although obviously, the most stunted children will have the highest risk of failing to respond to therapy, for relapse, and for mortality.

Infants <6 months — For infants under six months of age, any of the following criteria may be used to define SAM [8-11]:

●Weight-for-age Z-score (WAZ) <-3 SD

●Weight-for-length Z-score (WLZ) <-3 SD

●MUAC <11 cm (for ages 6 weeks to 6 months)

●Presence of edema

The threshold for admitting these infants to inpatient care is necessarily lower than for older children. (See 'Triage' below.)

Children ≥5 years — For children five years of age and older, anthropometric standards to define acute malnutrition in this age group have not been clearly defined, but it is reasonable to use body mass index (BMI)-for-age Z-score criteria to define severe wasting. Using BMI-for-age charts from the WHO, "thinness" (corresponding to moderate malnutrition) is defined as a Z-score <-2 SD and severe thinness (corresponding to severe malnutrition) is <-3 SD.

Although malnutrition is less common in this age group compared with younger children, it occasionally occurs, particularly in times of displacement or significant food insecurity. Severe malnutrition in these children necessitates a search for a severe underlying infection. In endemic areas, older children with kwashiorkor often have tuberculosis as their underlying diagnosis, while those with marasmus may be infected with tuberculosis, human immunodeficiency virus (HIV), visceral leishmaniasis, or a combination. Congestive heart failure from congenital or acquired disease (such as rheumatic fever) or nephrotic syndrome can also present with edema and should be considered in the differential diagnosis of kwashiorkor.

TRIAGE — Children between 6 and 59 months of age with severe malnutrition (marasmus and/or kwashiorkor) should be referred to a treatment center for a thorough clinical assessment to identify any medical complications. The first step is immediate assessment and attention to respiratory distress, altered mental status, dehydration, and other danger signs [12].

The treatment setting, nutritional intervention, and other medical management depends on the presence or absence of complications (algorithm 1):

●Uncomplicated SAM – The vast majority of children will have uncomplicated SAM, characterized by a good appetite and no significant, clinically evident medical complications; these children usually should be treated as outpatients in a supervised community-based feeding program, with regular follow-up. Their management is discussed in a separate topic review. (See "Management of uncomplicated severe acute malnutrition in children in resource-limited settings".)

●Complicated SAM – A small minority of children with severe malnutrition will have complicated SAM, characterized by medical complications such as sepsis, diarrhea with severe dehydration, significant skin breakdown with open ulceration, and/or a poor appetite. These children should generally be hospitalized and receive specific therapies for their acute illness(es) while nutritional rehabilitation is initiated; their care is complicated and resource intense, but good outcomes can be expected if they are managed with a sound systematic approach. The appetite is determined by an "appetite test," wherein they demonstrate an ability to successfully eat a moderate amount of ready-to-use therapeutic food (RUTF) under direct supervision; from a practical standpoint, this is the most useful criterion in determining whether a child can be treated at home. (See 'Ready-to-use therapeutic food appetite test' below.)

Other children who may need to be hospitalized include (but are not limited to) those who have not recovered after a trial of outpatient therapy, those with untreated HIV or tuberculosis infection that need to initiate definitive therapy, and those with challenging social situations (eg, those with challenges in accessing an outpatient therapeutic site reliably or those without caretakers able to provide frequent supervised feedings at home) [3,5].

For infants <6 months, the threshold for admission to inpatient care is necessarily lower than for older children, especially if the inpatient center can offer intensive counseling and assistance in resuming exclusive breastfeeding [5]. Although specific clinical trial evidence is lacking, the general approach to treatment is to provide closely supervised feedings with commercial infant formula or diluted F-100 formula (see 'F-75 and F-100 formula diets' below), with attempts at reinstituting or optimizing exclusive breastfeeding [5]. These infants have relatively high rates of morbidity and mortality as there are often a number of severe underlying social and biologic factors that have led to SAM at such a young age [13]. Outcomes for this population remain suboptimal due to these complexities, warranting particularly increased attention to this high-risk population [14,15]. (See 'Infants <6 months' below.)

OVERVIEW OF INPATIENT MANAGEMENT — The protocol for management of complicated SAM consists of three major overlapping phases: initial stabilization, rehabilitation, and follow-up. The approach is based on the disrupted physiology of the malnourished child (table 2) [16,17]. Most notably, the malnourished child has profoundly damaged gut function with decreased absorptive capacity, aberrant inflammation, and decreased protective barrier function that predisposes to bacterial and toxin translocation [18,19]. Other physiologic changes conserve energy (known as "reductive adaptation") by reducing physical activity and growth, reducing the functional reserves of organs, and reducing inflammatory and immune responses.

The management approach has evolved over decades of trial and error to become an international standard of care endorsed by the World Health Organization (WHO) [20-22]. Most of these recommendations reflect common practice and expert opinion and are not necessarily informed by randomized trial evidence [23]. Nevertheless, a systematic and organized approach to the care of these children will maximize the chances for recovery. In inpatient settings, the use of a specially designed checklist that improves adherence to the various elements of care helps to improve recovery rates [24]. These checklists should be developed and adapted to each local setting. An example of such a checklist is available here.

●Initial stabilization – The initial phase is a critical time with an emphasis on the acute recognition and treatment of life-threatening conditions, especially hypoglycemia, hypothermia, dehydration, and infection. Feedings are begun immediately and advanced as the rehabilitation phase begins. Modern therapeutic feeding products generally contain all necessary electrolytes and vitamins to correct most deficiencies and do not require specific supplementation.

●Rehabilitation – With the advent and widespread availability of ready-to-use therapeutic food (RUTF), the inpatient rehabilitation phase has been dramatically shortened for most children. Malnourished children usually can be discharged home within a week of admission, once steady weight gain and/or decreasing edema is observed, to complete rehabilitation with close outpatient follow-up. During the inpatient rehabilitation phase, the child's caretaker is trained to continue care at home and any social problems are addressed. Emotional and sensory stimulation of the child are continued throughout the initial and rehabilitation phases.

●Follow-up – In the follow-up phase, the physical, mental, and emotional development of the child are monitored after discharge.

INITIAL STABILIZATION PHASE — The initial stabilization phase is a critical time that emphasizes treatment of life-threatening conditions, including hypoglycemia, hypothermia, dehydration, and infection.

Treatment priorities include respiratory support, temperature control (warming), empiric antibiotics for infection, and rehydration. Feedings are begun in this period as soon as clinically safe. They are advanced as the child's appetite returns, which typically occurs during the first few days of refeeding.

Hypoglycemia — Hypoglycemia and hypothermia may occur with fasting of as short as four to six hours' duration in a malnourished child or can be precipitated by a serious systemic infection. These conditions may be associated with apnea. These disorders usually respond to early and frequent feedings and temperature control. Blood glucose levels should be checked if any concerning clinical signs are present, including hypothermia, apnea, anorexia, listlessness, or lethargy. Treatment for hypoglycemia should be initiated if the blood glucose is less than 3 mmol/L (54 mg/dL) [12,25], as follows:

●If the child is conscious, administer 50 mL of 10% glucose or sucrose solution (eg, one rounded teaspoon of sugar in three tablespoons of water) orally or by nasogastric tube, followed by feeding as soon as possible.

●If the child is unconscious, administer 10% dextrose or glucose solution, 5 mL/kg intravenously (IV; or by nasogastric tube if IV access is not possible).

●If oral, IV, or nasogastric administration is not possible, administer sublingually one teaspoon of sugar moistened with one to two drops of water, taking care to avoid aspiration. Repeat every 20 minutes to avoid relapse.

Hypokalemia and other electrolyte deficiencies often occur among severely malnourished children. However, specific serum measurements are rarely available in resource-limited settings. Moreover, specific supplementation generally is not necessary, because Rehydration Solution for Malnutrition (ReSoMal), oral rehydration solution (ORS) with or without potassium supplementation, and the therapeutic feeding products used for treatment of malnutrition will usually correct these deficiencies gradually and safely.

Hypothermia — If the body temperature is <35.5°C (96°F), the child should be warmed. This can be accomplished using a warm blanket or with an incandescent lamp directed on, but not touching, the child's body. If these options are not available, the child can be warmed by close contact with the caregiver's body. Hypothermia may be a sign of sepsis or may be caused by fasting.

Infection

Empiric antibiotics — All malnourished children in inpatient care should be treated empirically with a course of broad-spectrum antibiotics because many children with severe malnutrition have systemic infections, including bacteremia, urinary tract infections, and pneumonia [5,26,27], often without classic clinical signs such as fever, tachycardia, or tachypnea. If resources are available, blood and urine cultures should be obtained to guide optimal management but treatment should not be delayed while awaiting results.

●Rationale for empiric treatment – Formal studies are limited but have shown survival benefits when antibiotics are empirically included in the treatment regimen [28-31]. Moreover, empiric treatment is appropriate in malnourished children because of the high rates of underlying infections [32,33]. In addition, clinical symptoms and signs of infection are often absent in this population:

•Children with respiratory infections may present with tachypnea, retractions, and other signs of respiratory distress, but these are unreliable signs in malnourished children; their absence, as well as a normal chest radiograph or ultrasound, does not exclude the possibility of a significant respiratory infection.

•Septic shock may be difficult to distinguish from dehydration, and these conditions may coexist in the severely malnourished child, especially if diarrhea is present [17]. Helpful distinguishing clinical features include weak or absent pulses, which are likely to occur in septic shock rather than dehydration (although cold hands and feet may occur in either condition); thirst; and sunken eyes and fontanel, which are characteristic of dehydration and do not occur in sepsis (table 3). However, typical signs of dehydration (eg, lack of moisture of the mouth and poor skin elasticity) are not reliable in severely malnourished children. Moreover, assessment of perfusion also may be particularly difficult in patients with edema due to kwashiorkor. (See "Malnutrition in children in resource-limited settings: Clinical assessment".)

●Antibiotic selection – In our practice, we use the following approach for all hospitalized patients with SAM, unless microbiologic data are available to guide antibiotic selection:

•We generally begin all hospitalized children on ampicillin (50 mg/kg intramuscularly or IV every six hours) plus gentamicin (7.5 mg/kg intramuscularly or IV once daily) for a total of 7 to 10 days. For children who appear particularly ill or are in areas with high rates of antibiotic resistance, we use ceftriaxone (80 mg/kg intramuscular injection/IV once daily [34]) instead of ampicillin and gentamicin.

•For those children presenting with prolonged diarrhea, metronidazole (12.5 mg/kg orally every 12 hours [34]) is added as well. There is insufficient evidence to support empiric treatment with metronidazole for all children with SAM [35].

•For those children who recover quickly and are able to be discharged home before their parenteral antibiotic course is completed, the antibiotic regimen can be transitioned to oral amoxicillin (40 to 45 mg/kg orally every 12 hours), amoxicillin-clavulanate, or a third-generation cephalosporin to complete at least one week of antibiotics.

•However, if children remain hospitalized, even those with signs of apparent clinical recovery, we continue broad-spectrum parenteral antibiotics for at least 7 to 10 days due to the high rates of bacterial infection in children with complicated SAM.

This approach is more aggressive and systematic than the empiric antibiotic selection that has been traditionally recommended by the World Health Organization (WHO) for initial treatment of children with SAM. The WHO regimen consists of a five-day course of parenteral ampicillin and gentamicin for patients with complicated malnutrition (with chloramphenicol for nonresponders) or oral trimethoprim-sulfamethoxazole for those with uncomplicated malnutrition [17,36]. However, this component of the WHO protocol has not been updated in nearly 20 years and does not reflect the global rise in antibiotic resistance, the spread of HIV, the increasing availability of newer antibiotics, and the increasing acuity of those children that require inpatient treatment (as most children can now be treated in the community). Therefore, we use the more intensive antibiotic regimens described above for children who are hospitalized with complicated malnutrition. Prospective trials are ongoing to help define optimal treatment regimens [37].

Other medications and immunizations

●HIV infection and antiretrovirals – For children with HIV infection who are not already treated with antiretroviral drugs (ARV), these drugs should be started as soon as possible after stabilization of metabolic complications and sepsis [5]. Doses of ARV should be the same as those for children without malnutrition since there is insufficient evidence to suggest otherwise [38]. Those already taking ARV and/or opportunistic infection prophylaxis (co-trimoxazole, azithromycin, isoniazid, etc) should continue with their home regimens and compliance should be optimized. Children who have not been tested for HIV should have testing done at the earliest opportunity. (See "Screening and diagnostic testing for HIV infection" and "Diagnostic testing for HIV infection in infants and children younger than 18 months" and "Overview of antiretroviral agents used to treat HIV".)

●Antimalarials – In areas of high malaria prevalence, the possibility of malaria should be considered in those children who are symptomatic, ie, who have an acute febrile illness (see "Malaria: Clinical manifestations and diagnosis in nonpregnant adults and children"). Some practitioners and national protocols recommend antimalarials empirically for all children with SAM; in this setting, artemisinin-combination therapy is preferred (see "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children"). Others recommend that combination therapy be reserved for those in whom specific testing is positive; rapid diagnostic tests are generally sufficiently accurate (see "Laboratory tools for diagnosis of malaria"). Our personal approach is to reserve testing and treatment for those children with signs or symptoms suggestive of malaria. This is an area of management where no clear randomized trial data exist.

●Antihelminthics – Some national protocols also recommend that malnourished children should also receive treatment for intestinal helminthic infections once they are clinically stable and before discharge from care. This is a reasonable approach as these children often have high rates of intestinal helminth infections, and this may be an opportunity to provide this therapy for children who have entered the health system and may not otherwise receive this care. Nevertheless, it must be acknowledged that this is not based on any clinical trial data, and it remains unknown whether this helps children recover or remain free from relapse once recovered [29]. If specific testing for ova and parasites (or other helminths) is available, it can be used to help guide this decision but generally is not practical in most settings. (See "Mass drug administration for control of parasitic infections".)

●Antipyretics – Children with fever may be treated with standard doses of antipyretics (acetaminophen/paracetamol, ibuprofen, etc), although we generally reserve these for children with high fevers (38.5 to 39°C or higher [>102°F]) or for those who are particularly irritable, anorexic, or uncomfortable. There is a very small risk of renal toxicity (ibuprofen) or hepatic toxicity (acetaminophen/paracetamol) when using these medications, especially in children with kwashiorkor, but in general, the benefits outweigh the relatively low risk when dosed appropriately. Aspirin (acetylsalicylic acid) should never be used to treat fever or pain in malnourished children. (See "Fever in infants and children: Pathophysiology and management".)

●Immunizations – When a child is hospitalized for severe malnutrition, health care workers should take the opportunity to be sure the child is caught up on all routine childhood immunizations, following standard local vaccination schedules as for non-malnourished children, especially against measles. The immunizations should be administered after the child is stabilized but before hospital discharge, if possible. Immunization schedules of various countries are available through the WHO website.

Dehydration — Malnourished children often present with acute and persistent diarrhea and reduced homeostatic capacity to cope with water and potassium deficits. The pathogens responsible for this diarrhea are fairly similar to those of non-malnourished children in similar settings [39]. Diarrhea and severe dehydration are strongly and independently linked to increased mortality among severely malnourished children, so it is essential to manage these problems optimally [40]. As noted above, dehydration must be differentiated from septic shock, although the two conditions sometimes coexist (table 3).

Dehydration in the malnourished child should be treated with oral rehydration whenever possible [17,41,42]. In the setting of severe malnutrition, IV hydration may lead to overhydration and heart failure. As a result, IV infusion should be used only in the setting of severe hypovolemia or shock (table 4). (See "Treatment of hypovolemia (dehydration) in children in resource-abundant settings" and "Shock in children in resource-limited settings: Initial management", section on 'Volume and rate'.)

Rehydration Solution for Malnutrition (ReSoMal) — Rehydration Solution for Malnutrition (ReSoMal) is a type of ORS developed specifically for use in severely malnourished children. Although there is some evidence that ReSoMal may lead to hyponatremia, it remains the standard of care in the absence of a better alternative [43]. It consists of the standard WHO ORS that has been modified by decreasing sodium and increasing potassium, magnesium, zinc, and copper concentrations to account for the common electrolyte derangements in SAM that may be exacerbated by standard ORS (table 5) [29]. This solution is used to correct the hypernatremia and potassium deficiency that occur in severe malnutrition and is available commercially or can be made as follows:

●Dilute one packet of the standard WHO-recommended ORS into two liters of water (instead of one liter of water used for the standard ORS dilution)

●Add 50 g of sucrose (25 g/L); this is approximately four tablespoons of table sugar

●Add 40 mL (20 mL/L) of mineral mix solution (table 6)

In many clinical settings, this mineral mix solution may not be available and an approximation of ReSoMal must be made with locally available resources, even though the final micronutrient mixture is not ideal. In this case, the recipe above can be modified by adding approximately 50 mEq of an IV potassium chloride solution (eg, 40 mL of 10% potassium chloride or 50 mL of 7.5% potassium chloride) instead of the mineral-mix solution in the recipe above.

Oral rehydration solution — In many clinical settings, ReSoMal is not available and/or cannot be made from locally available ingredients. Historically, it was recommended that the standard undiluted WHO low-osmolarity ORS should not be used for rehydration of children with SAM. The rationale had been that ORS contains too much sodium and too little potassium for a typical child with malnutrition; however, there is a growing body of field experience and indirect evidence with ORS that suggests that it is nevertheless safe and effective for rehydration in this context [5].

Rehydration methods — If the child is able to drink, the ReSoMal or ORS solution is given by mouth. The required amount can be given as sips or by spoon or oral syringe every few minutes. However, malnourished children are weak and quickly become exhausted, so they may not take enough fluid voluntarily. If this occurs, the solution may be given slowly by nasogastric tube.

If adequate rehydration cannot be achieved through oral or nasogastric administration of ReSoMal or ORS alone, IV or subcutaneous fluids may be given. Half-strength Darrow's solution with 5% glucose is preferred [5,17]; the half-strength solution is created by diluting full-strength Darrow's solution (table 7) with an equal amount of 5% dextrose in water. It is also acceptable to use Lactated Ringer solution with 5% glucose or half-normal saline supplemented with sterile potassium chloride (20 mmol/L).

Hydration via the IV route should be approached cautiously since children with malnutrition are at risk for overhydration and heart failure. The initial bolus should be no more than 15 mL/kg and should be administered slowly over at least one hour. If there are signs of improvement (decrease in pulse and respiration rates), then a second bolus of 15 mL/kg may be given if the child is still unable to take this volume by mouth. If a severely malnourished child has been given a total of 30 mL/kg of IV fluids and reassessment suggests persistent dehydration, blood transfusion should be provided next. If hemoglobin measurements are not available (as is often the case in low-resource settings), the blood transfusion is given empirically because most such children will have significant iron deficiency anemia. (See 'Anemia' below.)

Malnourished children receiving IV hydration should be monitored closely for signs of overhydration or heart failure; for example, any time the child's respiratory rate or heart rate increases or does not decrease while receiving fluids, this should raise alarm. If the child does not improve after the first bolus, they may be suffering from shock rather than dehydration. (See "Malnutrition in children in resource-limited settings: Clinical assessment", section on 'Distinguishing sepsis from dehydration'.)

Target for volume replacement — A volume of 70 to 100 mL/kg body weight of ReSoMal or ORS usually is enough to restore normal hydration. This amount should be given over the course of 12 hours, starting with 5 mL/kg every 30 minutes for the first two hours and then 5 to 10 mL/kg per hour. This rate is slower than the rate of rehydration for children without severe malnutrition.

The child should be assessed at least hourly. The volume administered depends on the amount the child will drink, the volume of ongoing losses in stool and/or emesis, and any signs of overhydration, especially heart failure. Rehydration should be stopped if an increase in respiratory and/or pulse rates, engorgement of the jugular veins, increased liver size, or increasing edema (eg, puffy eyelids) occurs.

It may be difficult to know exactly when rehydration is complete, but signs may include when the child no longer is thirsty, produces urine, has improved skin turgor, and has improved mental status. Bedside ultrasound is also useful in assessing hydration status, comparing the ratio of the inferior vena cava with the descending aorta [44,45].

Once rehydration is complete, fluids given to maintain hydration should be based on the child's willingness to drink and the amount of ongoing losses in the stool. As a guide, children younger than two years of age should be given 50 to 100 mL (between one-fourth and one-half of a large cup) of ReSoMal after each loose stool and older children should receive 100 to 200 mL after each loose stool. This treatment is continued until the diarrhea stops and hydration status returns to normal.

Anemia — Children with severe anemia may require blood transfusion. The threshold for transfusion is hemoglobin ≤4 g/dL without cardiorespiratory symptoms or hemoglobin ≤6 g/dL with cardiorespiratory symptoms (or severe palmar pallor if hemoglobin measurements are not available). These transfusion thresholds are the same as for children without SAM in low-resource settings; there is no specific reason why they should be different in children with SAM [46].

When blood transfusion is indicated, give 10 mL/kg of fresh whole blood over three hours if there are no signs of heart failure (rather than the 20 mL/kg of whole blood that is used for children without SAM) [46]. If there are signs of heart failure, give 5 to 7 mL/kg of packed red blood cells over three hours instead.

Initial nutrition — Classically, inpatient feedings are initiated using a therapeutic milk formula. However, more recent practice is to allow children to begin immediately with ready-to-use therapeutic food (RUTF) if their appetite is good and no specific contraindications exist.

Ready-to-use therapeutic food appetite test — The key step is an appetite test, in which children are supervised in a calm setting to observe if they are able to eat approximately 30 grams of RUTF without vomiting or significant distress. If so, they can be started on RUTF immediately (algorithm 2) and transitioned directly to what was traditionally referred to as the "rehabilitation phase."

F-75 and F-100 formula diets — Children who do not "pass" the appetite test should be started on a therapeutic milk formula known as F-75, available through the United Nations Children's Fund (UNICEF), commercial sources, or prepared locally (table 8). F-75 is given at a daily dose of 80 to 100 kcal/kg (approximately 100 to 135 mL/kg), divided into frequent small feedings every two to three hours. The formula is fed in small amounts and at frequent intervals because intestinal motility and gastric acid production are decreased in severe malnutrition (table 2). A formulation of F-75 with reduced carbohydrate and lactose content did not improve outcomes during the stabilization phase in a rigorous multicenter trial in Kenya and Malawi [47]. Other alternatives to the standard therapeutic milk formulations have been attempted during shortages. As an example, a cow's milk porridge made with maize, soybean, vegetable oil, and sugar has been used effectively on a small scale in the Democratic Republic of Congo [48].

Infants can be fed orally using a cup and spoon; a dropper or syringe can be used in weaker infants. As a last resort, feeding may need to be given by nasogastric tube if the child has impaired consciousness or has vomiting, tachypnea, or painful stomatitis. For infants who are breastfed, continued breastfeeding should be encouraged during the refeeding phase, with supplements of expressed breast milk or F-75. Infants <6 months old should not be fed full-strength (undiluted) F-100, due to the high renal solute load [5]. (See 'Infants <6 months' below.)

Additional micronutrient supplementation beyond what is already contained in F-75, F-100, and RUTF formulations is generally unnecessary during the initial stabilization as these formulations contain all necessary vitamins and minerals needed to safely correct nearly all deficiencies, including the very common phosphorus, zinc, and vitamin A deficiencies. Specific exceptions may be needed under certain circumstances. (See 'Vitamin and mineral supplementation' below.)

Refeeding syndrome — On rare occasions, refeeding syndrome can complicate the nutritional recovery of children with severe malnutrition, typically within the first days or week of refeeding. The rapid increase in nutrient intake results in a switch from a catabolic state to an anabolic state. The ensuing surge in insulin secretion can result in hypoglycemia and influx of extracellular electrolytes into the intracellular space, which can lead to dangerously low extracellular concentrations of potassium, phosphate, and magnesium. In low-resource settings, it may be difficult to measure concentrations of electrolytes [49]. The electrolyte and mineral abnormalities may manifest clinically as lethargy, seizures, and muscle weakness, generally in the first few days of nutritional rehabilitation. Very rarely, well into the recovery period (eg, several weeks), impaired cardiac function, cardiomyopathy, and ultimately respiratory failure can occur. (See "Anorexia nervosa in adults and adolescents: The refeeding syndrome", section on 'Pathogenesis and clinical features'.)

While the incidence of refeeding syndrome in SAM is unknown, concern over this problem contributed to the development of the current composition of F-75 and F-100. It has been proposed that thiamine supplementation, or potentially further increasing the thiamine content of F-75 [50], may help avert both early- and late-onset cardiomyopathy. No clinical trials have been conducted to specifically test this hypothesis. Clinicians should be aware of the possibility of refeeding syndrome and late-onset cardiomyopathy but do not need to preemptively alter the standard feeding recommendations outlined above. In cases where refeeding syndrome appears to be developing, cautious correction of electrolytes is warranted (if available), and thiamine supplementation could be considered in cases of evolving cardiomyopathy.

REHABILITATION PHASE

Feeding advancement

Children ≥6 months — When a child taking F-75 is tolerating all or nearly all of the prescribed amount of feeds and is clinically stable (especially with regards to diarrhea), the diet can be advanced to a therapeutic feeding product that has higher levels of energy, protein, fat, electrolytes, and osmolality. The clinician should not wait for weight gain or resolution of edema before advancing feeds, because such improvements may not occur on F-75 feeds, although some overall clinical improvement can be expected. As the child's clinical status and appetite improves, our approach is to switch feedings from F-75 to either F-100 formula or ready-to-use therapeutic food (RUTF), as tolerated. The child should be fed at least five times daily during the rehabilitation phase [51,52], regardless of what type of food is used. Our approach is to gradually increase the volume of formula or RUTF by 10 to 15 kcal/kg/day to a target caloric intake of up to 150 to 200 kcal/kg/day.

We advocate repeating the appetite test using RUTF every one to two days at each step and advancing feeds to RUTF as soon as the child passes the test (algorithm 2) (see 'Ready-to-use therapeutic food appetite test' above). There does not appear to be any significant benefit of one feeding product over another [5,53], and rapid advancement to RUTF when tolerated allows for faster discharge, freeing up limited hospital resources, decreasing the risk of nosocomial infection, and also decreasing the likelihood that the caretaker will take the child home (or even abandon the child) against medical advice before therapy is complete. The most common form of RUTF is a peanut-based soft puree (paste) that is readily consumed by most infants six months and older, typically provided in sachets of 500 kcals (92 g) each (table 9 and picture 1) [4]. (See "Management of uncomplicated severe acute malnutrition in children in resource-limited settings", section on 'Ready-to-use therapeutic food'.)

For children who fail the RUTF appetite test, feeds can be advanced from F-75 to F-100, which contains 100 kcal/100 mL (table 8). If one of these therapeutic feeding products is not available, a modified rehabilitation feed, which can be formulated from whole milk, can be made (table 10). If the child successfully feeds on F-100, the RUTF appetite test should be repeated every one to two days, and feeds should be transitioned to RUTF as soon as the child passes the appetite test.

In settings where RUTF is not available and rehabilitation must be completed using F-100, a transition to traditional home diets can begin while the child is still hospitalized. This is done by gradually reducing and then stopping F-100, while adding or increasing the mixed diet until the child is eating a diet similar to what will be eaten at home.

The approaches described above are best established for children 6 through 59 months of age. For older children, specific therapeutic feeding regimens have not been clearly defined, but it is reasonable to use the protocols used for younger children, including rapid advancement to the standard RUTF as tolerated. Another formulation of RUTF, known as BP-100, comes in the form of a biscuit/bar that is especially well suited to older children. (See "Management of uncomplicated severe acute malnutrition in children in resource-limited settings", section on 'Ready-to-use therapeutic food'.)

Infants <6 months — The general medical care for severely malnourished infants younger than six months is very similar to that of older children. The main exception is that the overall goal is to return the child to a state of full exclusive breastfeeding whenever possible [5]. If breast milk production is insufficient, attempts should be made to increase (or restart) milk production using the supplementary suckling technique (figure 1), which has been demonstrated to be effective in stimulating enough milk production to achieve sufficient nutrition [54].

Nutritional therapy begins with as much breastfeeding as possible, supplemented with expressed breast milk, commercial infant formula, or F-75 as needed to ensure the infant gains weight every day.

Once clinically stable, the feeding can be advanced to either full breast milk feeds (if the child is able to gain weight steadily on breast milk alone), commercial infant formula, or diluted F-100 (prepared by diluting F-100 with an additional 30 percent water). Undiluted F-100 should not be given to young infants, because of its high renal solute load [5].

Unlike older children who can be fed RUTF at home following discharge from the inpatient facility, infants under six months of age should not be discharged home until they demonstrate sufficient weight gain on breastfeeding alone or with supplementation with commercial infant formula. An adequate supply of commercial formula at home should be ensured, as well as a plan to continue to resupply formula and prepare formula using clean water. The safety of RUTF or other therapeutic foods in children under six months of age has not been studied.

Vitamin and mineral supplementation — F-75, F-100, and RUTF all contain substantial amounts of supplemental vitamins and minerals needed for nutritional rehabilitation by most children, including sufficient phosphorus, zinc, and vitamin A to treat these common deficiencies. These vitamins and minerals are also contained in the World Health Organization (WHO) vitamin mix and mineral mix (table 11 and table 6). Providing additional supplementation beyond that contained in these therapeutic feeding products is not generally recommended, with the exception of iron (see below). Some observational evidence is emerging that children who clinically recover from SAM may still be left deficient in certain micronutrients, such as iron, vitamin A, vitamin B1 (thiamine), and vitamin B12 (cobalamin), but there are relatively few clinical data to support additional micronutrient supplementation at this time.

In particular, sufficient zinc is included in Rehydration Solution for Malnutrition (ReSoMal) and therapeutic foods used for severe malnutrition in amounts that exceed the 10 to 20 mg of zinc per day that is recommended for children with diarrhea [5]. Additional zinc dosing beyond what is already included in these formulas is thus generally considered unnecessary based on available evidence [5]. (See "Zinc deficiency and supplementation in children", section on 'Treatment of acute or persistent diarrhea'.)

●Iron – Although most severely malnourished children have some degree of iron-deficiency anemia, additional iron supplementation is not needed during the stabilization phase while the child is receiving F-75, during the first few days of F-100, and any time the child is receiving RUTF. Indeed, iron supplements may be dangerous to the child since transferrin levels are usually reduced, leading to toxicity and potentially increasing the risk of infection [17,20].

During the rehabilitation phase, children receiving F-100 should be supplemented with iron at a dose of approximately 3 mg/kg/day divided into two daily doses. This should generally be continued for two weeks. Children who switch to RUTF during the rehabilitation phase do not need additional iron supplementation.

Additional supplements beyond those contained in therapeutic foods are appropriate under the following circumstances:

●Vitamin A – High-dose supplementation of vitamin A (50,000 international units, 100,000 international units, or 200,000 international units, depending on age) is recommended for children with clinical evidence of overt vitamin A deficiency or recent measles or for those who will not receive therapeutic foods that are fortified as recommended in WHO specifications. (See "Overview of vitamin A", section on 'Targeted supplementation for disease'.)

●Thiamine – In certain parts of Southeast Asia, high rates of vitamin B1 (thiamine) deficiency have been observed among children born to mothers on traditional diets, which are low in thiamine. In this setting, a malnourished infant who appears to have septic shock may actually have beriberi and will clinically improve quite rapidly with thiamine [55]. Thiamine deficiency may also contribute to refeeding syndrome [56] and failure to recover from SAM generally. In settings with high rates of thiamine deficiency, additional supplementation of thiamine (eg, 50 to 100 mg daily) may thus be considered [50]. This may also be a significant problem in sub-Saharan Africa, but data from this location are relatively sparse [57]. (See "Overview of water-soluble vitamins", section on 'Infantile beriberi'.)

FAILURE TO RESPOND — When systematic treatment guidelines are followed, most severely malnourished children should show definite signs of improvement within a few days, followed by continued progress [17]. Children who fail to respond to treatment either fail to achieve the initial anticipated rate of improvement (primary failure) or deteriorate after an initial satisfactory response (secondary failure). When a patient fails to respond to treatment, care practices should be reviewed and the child should be reevaluated [17]. The objective is to identify a specific cause and to correct the problem.

Causes — Failure to respond may be due to the treatment environment or individual patient factors:

●Treatment environment – Hospitals in high-burden settings unfortunately often provide a suboptimal environment for malnourished children. As examples, staff may be insufficient or inadequately trained, scales may be inaccurate, feedings may be incorrectly prepared, the risk of nosocomial infection is high, and the child's caretakers are often burdened with many round-the-clock nursing tasks that they are unprepared to manage for prolonged periods. Moreover, even with optimal hospital care, many children will not make an optimal recovery [58]. This is part of the rationale to advance feedings to ready-to-use therapeutic food (RUTF) and discharge children as soon as possible to complete their recovery at home.

●Insufficient nutrition – Patients may fail to respond because they are fed insufficient food or have a vitamin or mineral deficiency [59]. Malabsorption of nutrients or rumination may contribute to lack of improvement.

●Infection – Children who fail to respond to nutritional treatment should be investigated for infection [17]. Malnutrition leads to increased susceptibility to infection because nutritional deficiency results in immunosuppression and often occurs in the setting of a home environment with poor sanitation. The most frequent infections include diarrhea, dysentery (with hematochezia), pneumonia, urinary tract infection, otitis media, skin infections, and tuberculosis. In endemic settings, tuberculosis, notably, can have its first and only manifestation as severe malnutrition, without the classic localized pulmonary or lymph node disease. Other infections include intestinal helminths, malaria, leishmaniasis, and HIV infection. (See "Persistent diarrhea in children in resource-limited settings".)

●Undiagnosed medical conditions – Children may fail to respond to treatment because they have a serious underlying condition. Malnutrition may result from a variety of conditions including unrecognized congenital abnormalities, inborn errors of metabolism, malignancies, immunologic diseases, and other diseases of the major organs.

Review of rehabilitation failure — Optimal practices should result in a case fatality rate of less than 10 percent [60]. To assess and optimize clinical practice at a health care facility, it is important to keep accurate records of all children who fail to respond to treatment and of all deaths. Data should include the child's age, sex, date of admission, weight-for-height (or -length) on admission, principal diagnoses, and treatment. If the child died, the date and time of death and apparent cause should be noted. These records should be reviewed periodically to identify areas for improvement. The timing of treatment failure or death can be helpful. As an example, deaths that occur within the first two days often are caused by hypoglycemia, unrecognized or mismanaged septic shock, or serious infection, whereas deaths that occur later often are caused by heart failure related to improper fluid management.

COGNITIVE AND FAMILY REHABILITATION — Severe malnutrition can result in delayed mental and behavioral development [61]. This delay likely is caused by significantly reduced brain growth, as reflected in reduced head circumference in malnourished compared with well-nourished children [61]. The effect on cognition and behavior is the most serious long-term result of malnutrition.

Environmental stimulation — Play programs that provide emotional and physical stimulation should start during rehabilitation and continue after discharge. These programs may reduce the risk of the child having some permanent intellectual disability and emotional impairment, although the direct evidence for this is relatively lacking [61,62].

Sensory deprivation should be avoided [17]. The child should be able to see and hear what is happening around him or her, and the face should not be covered. The child should never be restrained unless there is a risk of self-harm (eg, by pulling out a nasogastric tube or intravenous [IV] cannula). The mother or an alternate caregiver should stay with the child in the hospital and during rehabilitation. She should be encouraged to feed, hold, comfort, and play with her child as much as possible.

Children undergoing treatment for malnutrition should receive care in a cheerful environment. Toys should be available that are appropriate for the child's age and level of development. Play with other children is an important component of rehabilitation. Mothers or other caregivers should be encouraged to participate and can be trained to supervise play sessions.

Physical activity should be encouraged to promote the development of essential motor skills and enhance growth. Patients who are unable to move may benefit from passive motion of the limbs. As the child's nutritional status and general condition improve, the duration and intensity of physical activities should increase.

Parent education — Parents or other primary caregivers should receive education regarding the causes of malnutrition and its prevention. Breastfeeding is a particularly important and practical measure to prevent malnutrition, so all mothers should be educated to exclusively breastfeed infants for the first six months and to continue breastfeeding for at least the first two years of life. Parents should also be given education about an appropriate diet and sanitary feeding techniques, strategies to stimulate the child's mental and emotional development, and other parenting skills. Teaching should begin well before discharge. The mother should spend as much time as possible at the nutrition rehabilitation center with her child and should provide care, including food preparation, for her child under supervision. She should be taught how to treat or obtain treatment for diarrhea and other infections and to understand the importance of regular treatment for intestinal parasites.

DISCHARGE PHASE — During rehabilitation, preparations should be made to ensure that the child is fully reintegrated into the family and community after discharge. The family must be prepared to prevent recurrence of severe malnutrition. If possible, the home should be evaluated by a social worker or nurse before discharge to ensure an adequate environment. If the child is abandoned or conditions at the home are unsuitable, a foster home should be sought [17].

Transfer to outpatient care — Where quality outpatient care for malnutrition is available, children should be transferred from inpatient to outpatient care when medical complications including edema are resolving and the child appears clinically well and has a good appetite for ready-to-use therapeutic food (RUTF) [5]. The target intake for RUTF is 150 to 200 kcal/kg/day, and the child should be consistently taking at least 75 percent of this target before discharge. In the past, criteria for transfer to outpatient care depended on specific anthropometric variables [7,52,63], but these standards are no longer needed where specialized outpatient care for severe malnutrition is available.

For infants younger than six months, it is reasonable to transfer to outpatient care when weight gain on exclusive breastfeeding or replacement feeding is satisfactory (eg, weight gain more than 5 g/kg/day for at least three days) and the caregiver is linked with needed community-based outpatient care. (See "Management of uncomplicated severe acute malnutrition in children in resource-limited settings".)

Discharge from treatment — Children 6 to 59 months of age may be discharged from the outpatient treatment program when they meet a series of anthropometric, medical, and social criteria, as outlined in the table (table 12). The anthropometric criterion used for discharge from the outpatient treatment program typically uses the anthropometric criterion that was used for admission to the treatment program [5]. (See "Management of uncomplicated severe acute malnutrition in children in resource-limited settings", section on 'Discharge from treatment'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric malnutrition".)

SUMMARY AND RECOMMENDATIONS

●Classification of malnutrition – Severe acute malnutrition (SAM; also known as severe wasting or nutritional edema) in children can take the form of either marasmus (severe wasting) and/or kwashiorkor (edematous malnutrition), diagnosed by either weight-for-height Z-score (WHZ), mid-upper arm circumference (MUAC) criteria, and/or bilateral pitting edema (table 1). (See 'Classification by age and severity' above.)

●Assessment for complications – The initial assessment of a child with SAM begins with identification of those with clinical complications that require inpatient care; urgent attention to acutely life-threatening conditions such as hypoglycemia, hypothermia, and dehydration; and the detection and treatment of infection. Dehydration may be difficult to distinguish from septic shock in a malnourished child (table 3).

●Triage – For children 6 through 59 months of age, initial management depends on the presence or absence of complications and appetite (algorithm 1):

•Uncomplicated SAM – Children without clinical complications and with a good appetite can be treated as outpatients with ready-to-use therapeutic food (RUTF); management of this group is discussed in a separate topic review. (See "Management of uncomplicated severe acute malnutrition in children in resource-limited settings".)

•Complicated SAM – Children with one or more complications or with a poor appetite should be treated initially in an inpatient setting to permit management of the complications, rehydration, treatment with empiric intravenous (IV) antibiotics, and initiation of feeds. (See 'Triage' above.)

●Initial management

•Antibiotics – For all children with complicated SAM managed in resource-limited settings, we suggest empiric treatment with a course of broad-spectrum antibiotics rather than no antibiotics or symptom-based treatment (Grade 2C). Empiric antibiotic therapy is warranted because of the high rates of underlying infections in severely malnourished children and because clinical symptoms and signs of infection are often absent. In our practice, we treat with a 7- to 10-day course of antibiotics, which are given IV in hospitalized patients, and transition to oral antibiotics when the patient is transferred to outpatient care. (See 'Empiric antibiotics' above.)

•Rehydration – Children with SAM who are treated as inpatients often require rehydration, which is accomplished with oral rather than IV rehydration, when possible, to reduce the risk of overhydration and heart failure. The optimal solution for initial rehydration is Rehydration Solution for Malnutrition (ReSoMal), which is based on the standard World Health Organization (WHO) rehydration oral solution that has been modified by decreasing sodium and increasing potassium concentrations (table 5). Standard low-osmolarity oral rehydration solutions (ORS) may be used if ReSoMal is not available. (See 'Dehydration' above and 'Rehydration Solution for Malnutrition (ReSoMal)' above.)

●Feeding – After emergency conditions are treated, feedings should be initiated.

•Appetite test – The first step is to perform an appetite test with RUTF (see 'Ready-to-use therapeutic food appetite test' above). If the child does not pass the appetite test, feedings should begin using F-75 formula at a dose of 80 to 100 kcal/kg/day (table 8 and algorithm 2). (See 'Initial nutrition' above.)

•Feeding advancement – As the child improves, feedings are advanced to either F-100 formula or RUTF as tolerated. The child should be fed at least five times daily, and goals for intake are approximately 150 to 200 kcal/kg/day.

For most children, we suggest advancement of feeds to RUTF as soon as the child passes the RUTF appetite test (Grade 2C). Rapid advancement to RUTF allows for faster discharge, thereby reducing the risk of nosocomial infection, conserving health care resources, and decreasing the likelihood that the caretaker will take the child home (or even abandon the child) before therapy is complete. (See 'Rehabilitation phase' above.)

●Transfer to outpatient care – Where quality outpatient care for malnutrition is available, children should be transferred from inpatient to outpatient care when medical complications including edema are resolving and the child has a good appetite for RUTF and appears clinically well. For infants younger than six months, it is reasonable to transfer to outpatient care when weight gain on exclusive breastfeeding or replacement feeding is satisfactory (eg, more than 5 g/kg/day for at least three days). (See 'Transfer to outpatient care' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges William J Klish, MD, and Buford L Nichols, MD, who contributed to earlier versions of this topic review. The staff also acknowledges the help of Diana L. Culbertson, MS, MMSc, PA-C, for her help in preparing this article.