The majority of the articles cited below recommended a BCAA-free source of protein during acute illness however, recommendations vary in regard to the amount of BCAA-free protein. Age of the person, presenting symptoms and severity of symptoms seem to be determining factors. Ten clinical reports (F.104, F.44, F.45, F.73, F.20, F.105, F.51, F.76, F.75, F.426) and three expert opinions (G.50, G.39, G.82)  used a BCAA-free source of protein. The total amount of BCAA-free protein ranged from 1.0 to 4 g/kg/day (F.44, F.73, F.105, F.51, F.76, F.426, F.423). Currently available BCAA-free medical foods are listed in TABLE #7, Classification of Medical Foods for MSUD

Delphi 2: 

There was not consensus (83% of RD, but only 66% of MD respondents agreed) that, in individuals with MSUD who are hospitalized due to acute illness, the amount of BCAA-free medical food should be increased to 120-150% of the amount provided to the patient when well.

Comments: 150% may be excessive

The importance of increasing energy intake via calorically dense feeds was exhibited in 11 clinical studies (F.104, F.44, F.73, F.77, F.20, F.105, F.51, F.76, F.81, F.52, F.426) and 4 expert opinions (G.50, G.39, G.27, G.82). Energy recommendations indicated the following: 95 -150 Kcal/kg (neonates) (F.105, F.104, F.51, F.52), 1500 Kcal/m² (neonates and children) (F.73), 88 Kcal/kg (children) (F.76), and 150 to 200% of calculated energy needs (F.426)

Delphi 2:

There was consensus (83% of RD and 100% of MD respondents agreed) that, In individuals with MSUD who are hospitalized due to acute illness, energy recommendations may be 100-150% of the amount provided to the patient when well.

Comments: 150% may be excessive

A common finding during illness is dehydration and acid-base imbalance (F.80, F.45, F.85). A solution of 5 to 10% glucose was recommended to treat dehydration and correct acidosis (F.104, F.51, F.81) in 3 reports. A fluid intake of 150 ml/kg has been recommended (F.81). Caution must be taken to avoid fluid overload and cerebral edema by monitoring and adjusting electrolytes (F.85, F.426, F.423, G.47).

Delphi 1:

There was consensus (100% of all respondents agreed) that careful monitoring of hydration, electrolytes and neurological status is necessary to prevent cerebral edema.

Comments: mannitol and hypertonic saline may also be required.

There was consensus ( 91% of RD and 83% of MD respondents agreed) that IV fluids with 10% glucose should be provided at 1.5 – 2 times maintenance.

Comments: 2 times may be too much; need to monitor sodium: water balance; risk of brain edema is so great that need to evaluate carefully to determine if need fluid restriction; need intralipid 20% to meet remaining caloric needs; and may need higher % dextrose to reverse catabolism.

Evidence: Insulin was utilized to maintain blood glucose < 150 mg/dL (F.104) or 180 to 270 mg/dL (F.86) when pushing IV glucose. Studies reported a range of 0.04 to 0.13 U insulin per hour during surgery (F.127) and 0.05 to 0.3 U per hour during acute illness (F.44, F.75, F.426).

Delphi 1:

There was consensus (81% of RD and 83% of MD respondents agreed) that, to allow sufficient glucose infusion for anabolism, insulin may be required to prevent hyperglycemia:

Comments: the recommendation should be reworded to state “insulin may be needed.” Also, there is a need for blood glucose monitoring and individual assessment. Insulin would be needed when blood glucose > 150 mg/dL”.

Both enteral and parenteral nutrition have been used in the acute stage and during illness to aggressively supply needed calories to minimize catabolism. Twenty clinical reports (F.104, F.44, F.80, F.45, F.73, F.79, F.20, F.93, F.105, F.51, F.76, F.81, F.52, F.75, F.426, F.423, F.86, F.92, F.66, F.83) and 5 expert opinions (G.50, G.39, G.33, G.27, G.82) used enteral nutrition or a combination of enteral and parenteral nutrition management during acute illness. The decision regarding route and composition of solution/formula was based upon severity of symptoms at initial presentation or during acute illness. Length of intravenous therapy depended on the individual’s ability to tolerate formula by mouth or nasogastric tube. Enteral nutrition using a BCAA-free formula along with parenteral glucose and lipid solutions have been used until total requirements were able to be met enterally. Specialized BCAA-free parenteral solutions were used in 2 reports (F.104, F.51). The specialized solution in one report was 9% BCAA-free amino acids and 20 to 25% glucose or 9% BCAA-free amino acids plus 10% glucose and 10 to 20% fat emulsion (F.104).

Delphi 1:

There was consensus (100% of all respondents agreed) that parenteral nutrition providing adequate BCAA-free amino acids, glucose and lipids should be prescribed for comatose patients.

Comments: use the gut if possible, or a combination or enteral and parenteral. One site uses an enteral amino acid mixture because they cannot keep BCAA-free TPN in stock. Another stated that they do not use BCAA-free solutions for treatment. Others commented that it is important to provide BCAA as soon as patient can tolerate to prevent catabolism and monitor carefully at this point, and add ILE and VAL as indicated.

There was not consensus (100% of MD and 55% of RD respondents agreed) that 20% intralipid should be provided at 2 g/kg/day.

Comments: increase lipids as able to maximize calories, base the increase on energy to provide approximately 50% of requirement, which depends on the fluid and dextrose in the TPN. Aggressive treatment with glucose and lipid in the first hours of illness is often necessary as acquiring the specialty TPN solutions may take at least 24 hr.

There was consensus (100% of all respondents agreed) that enteral feeding, total or partial, should be introduced as soon as possible.

For individuals with MSUD who are at risk for metabolic crisis, it is important that access to stat monitoring for acid-base balance (F.104), blood glucose (F.104), and indicators of cerebral edema be available (F.51, G.35, G.43, G.44)). There should be access for rapid turnaround for plasma amino acid analyses to follow BCAA (F.75, F.104) and frequent monitoring of urinary α-ketoacids (G.44). Although there was no published evidence for optimal intervals for monitoring, there have been recommendations for every 2-24 hours for plasma BCAA (F.104), every 30-60 minutes for glucose when insulin was being given (F.104), every 6-24 hours for α- ketoacids (G.38). If hemofiltration was necessary success has been achieved with blood gas, hematocrit, total protein, sodium, calcium, phosphorus, urea, and creatinine monitored every 3-6 hours and amino acids every 12 hours (F.73). Inpatient treatment with possible admission to the critical care unit has facilitated monitoring of clinical signs as well as biochemical markers during serious catabolic illnesses (G.43)

Delphi 1:

There was consensus (82.5% of all respondents agreed) that ketone urine analysis strips should be used for home monitoring of ketones whenever clinically appropriate.

Delphi 2:

There was consensus (100% of all respondents agreed) that, during mild illness, physical and clinical signs of illness should be monitored and near consensus (92% of RD and 67% of MD respondents agreed) that, during mild illness, urinary α-keto acids. should be monitored.

Comments: it may not be possible to monitor α-keto acids, but keto sticks may be used for ketones. DPNH is hazardous and may not be appropriate for home use for α-keto acids

Dialysis or hemofiltration was described in 15 clinical reports. (F.104, F.45, F.73, F.79, F.20, F.93, F.105, F.52, F.85, F.75, F.91, F.423, F.86. F.92, F.66). Dialysis was recommended in one report when plasma LEU was > 2000 µmol/L (F.104). Another report used the LEU level of >1500 µmol/L to initiate hemofiltration (F.423). Continuous venovenous extracorporeal removal therapy was utilized when two out of three of the following were present: plasma LEU >1700 µmol/L, comatose state, gastrointestinal intolerance or danger of severe brain damage (F.73). Worsening neurological signs, despite appropriate nutritional therapy, was another indication for use (F.79, F.93). Dialysis has often been shown to be unnecessary for patients with MSUD because acute illness resulting in elevated plasma LEU has been managed using BCAA-free feedings (either enteral or parenteral), nutrition support to provide increased energy and supplemental ILE and VAL (G.50, G.43, F.51).

Delphi 1:

There was consensus (100% of all respondents agrees) that aggressive nutritional support including energy, fluid and BCAA-free amino acid mixtures should be used in conjunction with hemodialysis, peritoneal dialysis or exchange transfusion.

ILE and VAL supplementation during acute illness is used to help decrease LEU levels into the normal treatment range by providing substrate for protein synthesis and to prevent ILE and/or VAL deficiencies. This intervention has been supported by 8 clinical reports (F.104, F.44, F.73, F.51, F.76, F.75, F.426, F.83) and 5 expert opinions ( G.50, G.39, G.33, G.27, G.82). The amount of supplemental ILE and VAL varied, from minimal daily requirements (F.104), to 7 - 15 mg/kg (F.76) to 80 - 300 mg/day (F.44, F.73, F.51, F.81, F.52). When managing infants and children with severe decompensation, 150-300 mg/day of ILE and VAL were given if plasma levels were below 100 µmol/L (F.73). One clinic reported that glutamine and alanine (250 mg/kg/day each) have been utilized to promote LEU incorporation into protein for the sick neonate (F.51), and when plasma concentrations of tyrosine, histidine or threonine have been low, supplements of these amino acids have been recommended to normalize plasma levels (F.51).

Delphi 2:

There was consensus (92% of RD and 83% MD respondents agreed) that ILE and VAL supplementation should be used to help decrease LEU levels during illness.

There was consensus (100% of all respondents agreed) that ILE and VAL supplementation should be added or continued, if already used, during mild illness.

LEU derived from intact protein has typically been stopped during initial presentation and acute illness depending on symptoms. Seven clinical studies (F.104, F.105, F.51, F.426, F.83, F.75, F.44) and 3 expert opinions (G.50, G.39, G.33) have been successful in reintroduction of dietary LEU when plasma LEU reaches the upper level of the treatment range or when metabolic decompensation has been abated. This has usually been accomplished within 48-72 hours (F.104, F.51). Minimal details have been provided to recommend an amount of dietary LEU that should be introduced. Recommended ranges of protein, energy and BCAA are found in TABLE #4, Recommended Dietary PRO, BCAA and Energy Intake.

Delphi 1:

There was consensus (91% of RD and 83% of MD respondents agreed) that LEU from intact protein or amino acid mixtures should be introduced when plasma levels fall to the upper limit of accepted treatment range.

Comments: introduce sooner/may need longer; individually assess based on other indicators of catabolism; also based on the time passed without natural protein—usually begin ¼ usual goal for 24 hr and increase by ¼ to full goal both with time (24 hr), blood levels and/or DNPH.

There was consensus (100% of all respondents agreed) that, in patients with MSUD who are hospitalized due to acute illness, LEU (intact protein) should be re-introduced (slowly) by 48 hours.

There was near consensus (91% of RD and 67% of MD respondents agreed) that ILE and VAL supplementation should begin when plasma concentrations fall into the upper limit of the accepted treatment range.

Comments: three who did not agree commented that they would start supplementation sooner.

Although the use of human breast milk has been reported in the dietary management of a number of IMD, there are only two publications (F.664, F.43) that provide any outcome data for infants with MSUD. One study reports the results of a survey of 27  IMD centers in 15 countries (caring for over 8000 patients with IMD treated through dietary intervention). Successful demand feeding was reported in 17 infants with MSUD. The study did not report the percentage of breast feeding failures, but listed the most common problems incurred for the total population of IMD cases attempting breast feeding. The authors recommended strict monitoring, but did not feel their data suggested what the appropriate monitoring intervals should be (F.664). Another study reported the experience of breast milk feeding among seven patients with IMD, including a single patient with MSUD. Expressed breast milk was used for 2 months. Then, after one week of on-demand feeding, plasma BCAA levels were too high. On-demand breast feeding was attempted again at 3 months with good control, but was terminated because of the parental stress of frequent monitoring of the infant (F.43).

Delphi 2:

There was consensus (100% of RD and 83% of MD respondents agreed) that mature human breast milk with approximately 1 mg LEU/mL is an appropriate source of intact protein for infants with MSUD.

There was consensus (100% of all respondents agreed) that bottle feeding a combination of expressed breast milk and BCAA-free medical food requires determining the requirements for PRO, BCAA, energy and fluid for the infant with MSUD, and adjusting the mixture frequently based on anthropometric and biochemical monitoring.

There was near consensus (92% of RD and 67% of MD respondents agreed) that alternating between feeding at the breast and from the bottle (containing the BCAA-free medical food and any additional supplemental VAL, ILE and energy) can be successful if the infant with MSUD has close biochemical and anthropometric monitoring..

Two reports (F.20, F.426), one review (F.83) and four expert opinions, (G.26, G.33, G.44, G.27) provided interventions to be used in non-critical illness. Sick day regimens included removal of natural protein for 1- 2 days with gradual increase to 1 g/kg plus energy intake of 100 to 170 kcal/kg (F.20, F.426). Oral glucose solutions were recommended to increase energy intake. The use of nasogastric feeding was recommended if the individual is unable to consume adequate intake orally (F.83). Specific emergency guidance for caregivers and ED personnel were also recommended (G.44)

Delphi 1:

There was consensus (100% of all respondents agreed) that that guidelines for “sick day, at home” management the guidelines should:

• Be individualized
• Include appropriate guidelines for monitoring α-ketoacids and clinical status
• Include appropriate guidelines for decreasing BCAA intake
• Include appropriate guidelines for maintaining fluid and energy intake
• Include emergency contact information

There was consensus (100% of all respondents agreed)  that intact PRO should be reduced by 50-100% for at least 24 hours with replacement by BCAA-free medical food and additional energy sources.