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Abstract

Inherited metabolic disorders (IMDs) are a heterogeneous group of rare single-gene disorders caused by enzyme defects that disrupt biochemical and metabolic pathways. Acute metabolic decompensation is a medical emergency that can be fatal if untreated. It can be triggered by catabolic stressors such as fasting, infection, surgery, pain, bleeding, or exposure to anesthetic agents. Traumatic injury in particular can precipitate IMD life-threatening crises. The risks of complicating surgical interventions can be reduced by careful perioperative management of fluids, nutrition, and medications under the guidance of a biochemical genetics specialist. Management of IMD metabolic emergencies is often complex, and trauma and surgical providers may only have limited access to specific protocols. Without prompt recognition and treatment, patients with IMDs are at high risk of poor outcomes in trauma or surgical settings. Optimal management requires early consultation with a metabolic specialist and a coordinated multidisciplinary team. This review highlights key principles and resources to enhance recognition and management of IMD metabolic crises for trauma and surgical teams.

Keywords

acute metabolic decompensation catabolism inherited metabolic disorders surgery traumatic injury

Introduction

Inherited metabolic disorders (IMDs) are a heterogeneous group of single-gene disorders that affect biochemical and metabolic pathways.¹ Although each individual IMD is rare, collectively they affect ∼1 in 780 live births, and the number of known IMDs has progressively expanded.^2,3 While newborn screening (NBS) can facilitate the early detection and diagnosis of a subset of IMDs, NBS is only done for a few IMDs. Inherited metabolic disorders can be classified as small- and large-molecule disorders. Small-molecule IMDs include fatty acid oxidation disorders (FAODs), urea cycle disorders (UCDs), organic acidemias (OAs), aminoacidopathies (AAs), and mitochondrial diseases (MitoD) (Table 1).⁴ Large-molecule IMDs include lysosomal storage disorders and peroxisomal disorders.⁴

Table 1.

Common Categories of Small-Molecule Inherited Metabolic Disorders

Fatty acid oxidation disorders (FAODs)	Urea cycle defects (UCDs)	Organic acidemias (OAs)	Aminoacidopathies (AAs)	Mitochondrial diseases (MitoD)
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency	Carbamoyl phosphate synthetase I (CPS I) deficiency	Propionic acidemia (PA)	Maple syrup urine disease (MSUD)	Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency	Ornithine transcarbamylase (OTC) deficiency	Methylmalonic academia (MMA)	Tyrosinemia	Myoclonic epilepsy with ragged red fibers (MERRF)
Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency	Argininosuccinate synthetase (ASS) deficiency (Citrullinemia type 1)	Isovaleric acidemia (IVA)	Homocystinuria	Kearns-Sayre syndrome (KSS)
Systemic primary carnitine deficiency (CDSP)	Argininosuccinate lyase (ASA) deficiency	Glutaric acidemia (GA)	Nonketotic hyperglycinemia (NKH)	Leigh syndrome
Carnitine palmitoyltransferase 1 (CPS1) deficiency	Arginase deficiency	3-methylcrotonylglycinuria (3-MCG)
Carnitine palmitoyltransferase 2 (CPS2) deficiency		3-methylglutaconic aciduria (3-MGA)

The clinical manifestations of IMD are variable and can involve multiple organ systems to cause problems in children and adults.^5,6 In a subset of IMDs, symptoms can be managed and sometimes prevented but lifelong therapy is typically required.⁵ Clinical features can generally be divided into acute and chronic. In general, small-molecule IMDs can precipitate rapid, life-threatening crises under catabolic stress, such as traumatic injury or surgical intervention.⁷ In contrast, large-molecule IMDs typically follow a more chronic, progressive course and are less likely to cause sudden metabolic collapse in the acute perioperative setting.⁷ Accordingly, this review focuses on small-molecule IMDs that predispose patients to acute metabolic decompensation.

Acute decompensation in small-molecule IMDs can be triggered by multiple factors (Table 2) to cause medical emergencies that can be fatal if untreated. Such crises often manifest as hypoglycemia, hyperammonemia, seizures, encephalopathy, cerebral edema, lactic acidosis, rhabdomyolysis, and cardiac arrhythmias and failure.⁷ These complications can arise during perioperative care and be fatal if not anticipated. Perioperative settings that can be triggers include prolonged fasting (nil per os status), blood loss, transfusion, anesthetic choice, and certain medications (Table 2).^8-11 Traumatic injuries and surgery can cause metabolic crises because of catabolism (Table 2).^9,12 Surgery can be a catabolic trigger, and anesthetic agents must be selected based on the specific underlying IMD. Thus, it is crucial in trauma and surgical care to recognize the risk of metabolic crisis. When surgical intervention is required, meticulous perioperative management of fluids and medications under the guidance of a biochemical genetics specialist is essential.¹³

Table 2.

Common Perioperative Triggers of Acute Metabolic Decompensation

Triggers
Prolonged fasting
Fever
Infection
Trauma
Surgery
Anesthesia
Corticosteroids
Prolonged or vigorous exercise
Blood transfusion
Pregnancy

Management of metabolic emergencies in IMDs can be complicated, and access to protocols may be difficult for surgical providers to obtain. Importantly, surgical management of traumatic injuries without access to such protocols can put patients with IMDs at high risk of poor outcomes.^13,14 Prompt recognition and timely intervention under the guidance of a metabolic specialist can be lifesaving. Optimal outcomes may require a coordinated, synergistic multidisciplinary approach that includes trauma surgery, medical and biochemical genetics, nephrology, pharmacy, dieticians, and intensive care providers. This review aims to improve the awareness and resources needed by surgical teams by highlighting the recognition and management of metabolic emergencies in IMDs. While this review introduces commonly used management approaches and frequently used medication and fluid doses, these should always be tailored to the individual case and carefully reviewed in collaboration with a biochemical geneticist and the surgical team.

Trauma and Perioperative Considerations

Acute metabolic decompensation of IMDs can be fatal if treatment is delayed. For IMD patients, an acute physical stressor—such as prolonged fasting, fever, infection, and traumatic injury—can initiate a cascade of metabolic disturbances that rapidly perturb metabolic homeostasis (Table 2).^7-9,12,13 Muscle breakdown, commonly seen in crush injuries or major orthopedic trauma, can cause the dangerous release of proteins and amino acids into the circulation. Additionally, the physiologic stress response to trauma induces a catabolic state that increases endogenous protein breakdown.¹⁵ Required surgical intervention can also exacerbate catabolism due to the combined effects of anesthesia, fasting, tissue injury, and systemic stress.^9,12 Combinations of these factors can precipitate catabolic crises and lead to rapid neurologic deterioration, cerebral edema, and death.⁷

Although different IMDs may require disease-specific management, several general principles can help guide acute care (Table 3). In traumatic injuries, it can be challenging to diagnose underlying IMDs, particularly in de-identified individuals. This is why patients with IMDs should carry emergency letters and wear medical alert bracelets.^16,17 If an IMD is suspected or confirmed, a metabolic genetics provider should be contacted immediately (Table 3). If an in-house biochemical genetics consultation is not available, a tertiary care center with biochemical or clinical genetics expertise should be contacted promptly to discuss management. The need for transfer to a tertiary care center with metabolic expertise should be determined on a case-by-case basis in discussion with a biochemical genetics provider, and transfer should be considered when clinically indicated. If the patient is clinically unstable for transfer and requires urgent surgery, it is essential to maintain close communication with a biochemical genetics provider before and during the procedure to ensure optimal metabolic management.

Table 3.

Acute General Management Strategies for Acute Metabolic Decompensation

Intervention	Rationale
Consult biochemical genetics	To ensure expert guidance for specific management
Discontinuation of natural protein intake (first 24 h)	To halt catabolism and prevent accumulation of offending amino acids
Intravenous dextrose-containing fluids (eg, D10 normal saline) at 1.5 times maintenance rate, achieving a glucose infusion rate (GIR) of 8 to 10 mg/kg/minute	To provide calories to promote anabolism, reducing endogenous protein breakdown
*Exception: High-glucose infusion should be avoided in patients with pyruvate dehydrogenase deficiency, mitochondrial dysfunction, or those on ketogenic therapy, due to the risk of lactic acidosis
Intravenous intralipid infusion	To supply additional non-protein calories for anabolic support
*Exception: It is contraindicated in fatty acid oxidation disorders (FAODs)
Metabolic total parenteral nutrition (TPN)	To maintain nutritional needs while avoiding protein catabolism
Specialized metabolic formulas	To reduce levels of offending amino acids and maintain target levels of other essential amino acids
Continuous renal replacement therapy (CRRT)	To rapidly remove toxic metabolites

The primary therapeutic goal is to halt catabolism and promote anabolism (Table 3).⁷ During the first 24 h, protein intake is usually withheld to minimize catabolic stress.^18-20 Initial management with prompt administration of dextrose-containing intravenous fluids can provide calories and suppress catabolism (Table 3).^21-24 Intravenous D10 normal saline at 1.5 times maintenance rate is often used, to achieve a glucose infusion rate (GIR) of 8 to 10 mg/kg/minute.^21-24 The goal is to maintain normoglycemia; but if hyperglycemia develops, an intravenous insulin infusion can be initiated to promote anabolism and preserve the GIR, rather than decreasing the glucose delivery if clinically indicated.²⁵ Intravenous intralipids may be added for additional caloric support (Table 3), except in FAODs (Table 4), where they are contraindicated.^21-25 When intralipid therapy is used, serum triglyceride levels should be monitored. Lactated Ringers’ (LR) solution should generally be avoided due to its risk of exacerbating lactic acidosis and its lack of adequate dextrose content. However, LR is strictly contraindicated in MitoD for the same reason (Table 4).^26,27 Administration of hypotonic fluids also should be avoided because they can cause cerebral edema in some IMDs (Table 4).²⁵ Intravenous bicarbonate may be required to correct metabolic acidosis in some IMDs such as OAs and MitoD (Table 1), especially if the patient does not improve with the initial fluid management.^23,26,27 Excess bicarbonate should be avoided because it may cause hypernatremia, cerebral edema, and even cerebral hemorrhage.²⁸

Table 4.

Avoidable Practices in Acute Metabolic Decompensation

Don’t	Rationale
Don’t use lactated Ringers’ (LR) solution in mitochondrial diseases (MitoD)	It can exacerbate lactic acidosis
Don’t use hypotonic fluids in acute metabolic decompensation	They may exacerbate cerebral edema
Don’t administer intravenous intralipid to patients with fatty acid oxidation disorders (FAODs)	Intralipid cannot be metabolized in FAODs
Don’t administer high-glucose infusion to patients with pyruvate dehydrogenase deficiency, mitochondrial dysfunction, or those on ketogenic therapy	It may exacerbate lactic acidosis
Don’t delay treatment while awaiting test results	Treatment should begin immediately
Don’t give anesthetic agents without consulting a metabolic genetics specialist	Certain anesthetic agents pose risks; review anesthetic plans in advance with a metabolic genetics specialist

Another part of the acute care of IMDs is the rapid removal of toxic metabolites (Table 3). Continuous renal replacement therapy (CRRT) is an effective way to urgently clear toxic metabolites, but it requires early nephrology consultation and placement of a vascular catheter for access.²⁹ In addition, disorder-specific medications that enhance elimination of toxic metabolites (eg, nitrogen scavengers for hyperammonemia) should be initiated if clinically indicated.^22,25 Since pain and associated sympathetic activation can be stressors that accelerate catabolism, effective pain management is an important component of care. Labored breathing and tachypnea can also increase catabolism. Therefore, intubation with ventilation support should not be delayed, accompanied by adequate sedation and analgesia when clinically indicated.^9,13

When treatment for IMDs begins, laboratory evaluation should be performed in parallel; however, therapy should never be delayed while awaiting test results (Table 4).³⁰ A typical initial lab workup for IMD acute metabolic crisis includes blood glucose, blood gas analysis, lactates, electrolytes, anion gap, and plasma ammonia (Table 5).^21-24,30 In traumatic injuries, blood creatine kinase should also be obtained to assess for rhabdomyolysis in cases of FAODs (Table 5).²¹ Urinalysis is used to detect to the presence of ketones and myoglobin. Plasma amino acid analysis is crucial in AAs, such as maple syrup urine disease (MSUD).²⁴ Because traumatic injuries increase the risk of soft tissue infection and sepsis—and infection itself is a potent trigger for catabolism—an infectious workup is also essential (Table 5).

Table 5.

Initial Workup for Acute Metabolic Decompensation in Traumatic Injury

Workup	Rationale
Blood glucose	Hypoglycemia is common and life-threatening in fatty acid oxidation disorders (FAODs)
Blood gas analysis	To assess pulmonary and acid-base status
Lactate	Lactic acidosis is common in primary and secondary mitochondrial dysfunction
Electrolytes	Electrolyte disturbances are frequent during management of acute metabolic decompensation
Anion gap	Anion gap metabolic acidosis is a characteristic of organic acidemias (OAs)
Ammonia	Hyperammonemia is common and life-threatening in urea cycle disorders (UCDs) and organic acidemias (OAs)
Creatine kinase	To assess for rhabdomyolysis, a complication of FAODs
Urinalysis	To evaluate for ketones and myoglobin in urine
Infectious workup	Traumatic injuries increase the risk of infection and sepsis; infection is a potent trigger for catabolism

Patients with IMD are at increased risk of anesthesia-related complications. Careful preoperative consultation with an anesthesiologist with a metabolic genetics provider is crucial (Table 3).^9,13 In general, preoperative fasting should be minimized, and adequate glucose should be administered to prevent catabolism. Dextrose-containing intravenous fluids (eg, D10 normal saline) are preferred, and LR solution should be avoided—particularly in MitoD—because of its potential to exacerbate lactic acidosis (Table 4).^26,27 While a higher infusion rate (eg, 1.5 times the maintenance rate) of D10 normal saline or D10 half normal saline is generally ideal to achieve an adequate GIR, fluid management should be tailored on an IMD-specific basis. For example, some IMDs cause cardiomyopathy and heat failure in OAs as well as cerebral edema in MSUD. To avoid volume overload, a more concentrated dextrose-containing fluid (eg, D12.5 or D15 normal saline) at a relatively slower rate may be needed.²¹ In patients with pyruvate dehydrogenase deficiency, mitochondrial dysfunction, or those on ketogenic therapy, high-glucose infusion should be avoided because it may exacerbate lactic acidosis (Table 4).^26,27 While dextrose fluids containing up to 10% dextrose can be infused through peripheral intravenous catheters, higher concentrations of dextrose require a central intravenous catheter.³¹ That said, emergent dextrose infusion should not be delayed. Anesthetic agents must be selected with caution due to their potential adverse effects in metabolic disorders, and anesthetic plans should be discussed in advance with an anesthesiologist and a metabolic genetics specialist (Table 4).^9,13 For instance, propofol is contraindicated in both MitoD and FAODs.^26,27,32 Corticosteroids should also be used cautiously because they promote catabolism and may precipitate metabolic crisis (Table 2).³³ Absorption of blood extravasated into tissues can trigger decompensation of some IMDs because of absorbed protein (Table 2).¹¹ Communication with a metabolic specialist during surgery along with serial laboratory monitoring can help optimize fluid and medication management. A suggested management algorithm of traumatic injury in patients with IMD is summarized in Figure 1.^21-24,30

Figure 1.

Algorithm for Management of Traumatic Injury in Patients With Inherited Metabolic Disorders

Specific Scenarios

Fatty Acid Oxidation Disorders (FAODs)

Fatty acid oxidation disorders result from defects in either mitochondrial β-oxidation or the fatty acid transport through the carnitine transport pathway (Table 1).^34,35 Depending on the subtypes—short-chain, medium-chain, or long-chain—common clinical manifestations include non- or hypoketotic hypoglycemia, skeletal and cardiac muscle involvement (eg, muscle cramps, rhabdomyolysis, cardiomyopathy, and arrhythmia), and, more rarely, encephalopathy.^34,36,37

Because individuals with FAODs cannot utilize ketone bodies as an essential energy source during catabolic stress such as fasting, infection, and surgery. Fatty acid oxidation disorders can cause non- or hypoketotic hypoglycemia (Table 2). High-energy-dependent organs, including skeletal and cardiac muscle, and the brain, can be particularly affected in FAODs.^34,37 To promote anabolism and prevent hypoglycemia, it is essential to administer a higher GIR using dextrose-containing fluids (eg, D10 normal saline) (Table 3).^21,37 Importantly, intralipids are contraindicated in FAODs (Table 4). Carnitine supplementation may be beneficial when plasma carnitine levels are deficient, to prevent secondary carnitine deficiency by enhancing renal clearance of accumulated levels of abnormal acylcarnitine compounds.^21,37 However, intravenous carnitine administration can be contraindicated in long chain FAODs because of its potential to precipitate serious cardiac complications, including life-threatening arrhythmias.³⁸ In cases of rhabdomyolysis, aggressive hydration is indicated to prevent renal injury.²¹ Conversely, in patients with evidence of heart failure, fluid volume must be minimized to avoid volume overload.²¹ Anesthesia with propofol should be avoided in FAODs because propofol contains long-chain fatty acids, which cannot be adequately metabolized and increases the risk of propofol infusion syndrome (PRIS).³²

Urea Cycle Disorders (UCDs)

The urea cycle is responsible for ammonia detoxication (Table 1). In UCDs, defects in any of the enzymes involved lead to impaired ammonia clearance, resulting in hyperammonemia, particularly under catabolic stress.²⁵ Elevated ammonia level can precipitate acute encephalopathy, irreversible cerebral damage, coma, and even death.²⁵ Respiratory alkalosis can be an early indicator of UCDs, in contrast to the metabolic acidosis commonly observed in OAs, which may also present with hyperammonemia (Table 5).^20,25 In UCDs, elevated ammonia levels cause respiratory alkalosis from hyperventilation triggered by stimulation of the central respiratory drive in the brain. To prevent irreversible neurological injury and cerebral edema, it is crucial to reduce plasma ammonia level without delay.

In patients with UCDs presenting with acute hyperammonemia, all protein intake should be initially withheld for 24 h to minimize catabolism, and dextrose-containing intravenous fluids should be initiated to promote anabolism (Table 3).^20,22,25,39 Continuous renal replacement therapy is a key intervention for rapid removal of increased levels of ammonia.²⁹ In addition, nitrogen scavenger therapy (eg, Ammonul, a combination of sodium phenylacetate and sodium benzoate) is a cornerstone of medical management in acute hyperammonemia. These nitrogen scavengers lower ammonia levels by phenylacetate conjugating with glutamine to form phenylacetylglutamine and benzoate conjugating with glycine to form hippurate.^22,40 Since these conjugated products are excreted in the urine, adequate renal function is essential for their efficacy. Importantly, nitrogen scavengers are specifically indicated for UCDs and should only be used under the supervision of a metabolic geneticist because nausea and vomiting, hypokalemia, and hypernatremia can be common side effects. Prophylactic use of antiemetics (eg, ondansetron) is recommended before boluses of these nitrogen scavengers.^22,40 The high sodium load in Ammonul increases the risk of hypernatremia. Hypokalemia is also commonly observed and requires close potassium monitoring and supplementation. Also, phenylacetate can cause hepatotoxicity. Arginine is an essential amino acid that participates in the final step of the urea cycle, where it is converted by arginase into urea and ornithine. Arginine supplementation is used in treating most UCD crises to help preserve residual urea cycle activity, except in arginase deficiency, in which it is contraindicated (Table 1).²⁵ As a precursor of nitric oxide, arginine can promote vasodilation and lead to hypotension; so that it should be used with caution in patients who are hemodynamically unstable.

Organic Acidemias (OAs)

Organic acidemias are characterized by the accumulation of toxic organic acid metabolites and increased urinary excretion of organic acids (Table 1). Clinically, these disorders typically present with anion gap metabolic acidosis, ketosis, and hyperammonemia.^18,19,23,41 The clinical spectrum of OAs is broad, ranging from encephalopathy, seizures, developmental delay, failure to thrive, and to systemic complications such as cardiomyopathy, arrhythmia, pancreatitis, pancytopenia, and osteoporosis.^18,19

The key management of OAs is to prevent endogenous catabolism and promote anabolism (Table 3). Dextrose-containing intravenous fluids should be initiated and when a higher GIR is required, lactate levels should be monitored because lactate can accumulate due to secondary mitochondrial dysfunction caused by a potential interference with tricarboxylic acid (TCA) cycle entry and inhibition of pyruvate dehydrogenase by toxic metabolites.¹⁸ In such cases, insulin infusion may be needed to maintain normoglycemia.^18,19,23,41 Intralipid may be necessary as an alternative calorie source.^18,19,23 If metabolic acidosis is pronounced, intravenous bicarbonate therapy may also be needed. However, excess bicarbonate administration should be avoided because it may cause hypernatremia and cerebral edema, especially in patients with hyperammonemia.^23,28

Similar to UCD hyperammonemia may occur in OAs (Tables 1 and 5). The underlying mechanism involves the accumulation of CoA derivatives of organic acids, which inhibit the synthesis of N-acetylglutamate (NAG)—the essential allosteric activator of carbamoyl synthetase 1 (CPS1) in the liver.^25,42 Impaired NAG formation consequently reduces CPS1 activity, leading to impaired ureagenesis and ammonia accumulation.^25,42 For the treatment of hyperammonemia in OA, N-carbamylglutamine (carglumic acid), a structural analog to NAG synthetase, can serve as an obligate allosteric activator of CPS1. By restoring CPS1 activity, carglumic acid can facilitate ammonia detoxication. Similar to UCD, nitrogen scavengers are also effective for hyperammonemia in OA.^18,19

Maple Syrup Urine Disorder (MSUD)

Maple syrup urine disorder is an autosomal recessive AA caused by a deficiency in the branched chain alpha-ketoacid dehydrogenase complex, which breaks down branched-chain amino acids (BCAAs) (Table 1).^43,44 In patients with MSUD, impaired degradation of BCAAs (isoleucine, leucine, and valine) can cause accumulation of neurotoxic levels of leucine and coma. Without prompt treatment, acute metabolic decompensation in MSUD triggered by trauma or other factors can lead to cerebral edema and death due to the toxic accumulation of leucine.^24,43

The primary goal of managing MSUD is to halt catabolism and promote anabolism to decrease dangerous leucine levels (Table 3).^24,45 This is done by withholding natural protein to limit increases in BCAAs, especially leucine. It is critical to provide calories to prevent further catabolism by using dextrose-containing intravenous fluids (eg, D10 normal saline), intralipid, metabolic total parenteral nutrition, and specialized metabolic formulas with appropriate levels of BCAAs.^24,45 Dangerously high leucine levels can be lowered rapidly though CRRT which requires timely nephrology consultation and placement of a vascular catheter for CRRT access.^24,29

Mitochondrial Diseases (MitoD)

MitoD are a group of IMDs caused by mitochondrial dysfunction (Table 1). Because mitochondria are the “powerhouses” of the cell, generating cellular energy, patients with MitoD are unable to utilize energy efficiently, resulting in multisystemic manifestations. Lactic acidosis is common because impaired conversion of pyruvate to acetyl-CoA limits entry into the TCA cycle, leading to lactate accumulation and a shift toward anaerobic metabolism.^26,27

A major goal in management of MitoD crises is prevention of catabolism (Table 3). However, careful medication and fluid selections are needed to avoid adverse effects (Table 4). Lactated Ringers’ solution should be avoided in MitoD crises because of its risk of exacerbating lactic acidosis (Table 4) metabolism.^26,27 Dextrose-containing fluids are administered to suppress catabolism. However, MitoD patients may not tolerate high GIR due to TCA cycle dysfunction, which can cause lactic acidosis. In such cases, insulin infusion may be required to maintain normoglycemia and minimize further lactate accumulation. Also, MitoD patients are managed with ketogenic diets for seizure control, in whom exogenous dextrose administration can interfere with therapy and should be limited.^26,27 Medications known to impair mitochondrial function, such as propofol, metformin, aminoglycosides, and valproic acid, should be avoided when possible (Table 6).^26,27,46 Caution must be used with muscle relaxants in patients with MitoD with a preexisting myopathy or decreased respiratory derive. Particularly, depolarizing muscle relaxants such as succinylcholine should be avoided due to hyperkalemia and myotonic risks (Table 6).^26,27,46

Table 6.

Selected Medication Cautions in Mitochondrial Diseases (MitoD)

Medication	Concern
Aminoglycosides	Hearing loss
Metformin	Inhibit mitochondrial respiratory chain complex I
Lactated Ringers’ solution	Lactic acidosis
Propofol	Propofol infusion syndrome (PRIS)
Statin	Myopathy
Succinylcholine	Myopathy, respiratory drive depression, and hyperkalemia
Valproic acid	Liver failure, especially in POLG-related disorders

Useful Website Resources for Trauma and Surgical Providers

Management of metabolic emergencies in IMDs is complex, and trauma and surgical providers may have limited access to appropriate protocols. Immediate consultation with a metabolic specialist is essential to guide treatment. However, the following free online resources are valuable for understanding and reviewing the management of metabolic emergencies in IMDs.

New England Consortium of Metabolic Programs (https://www.newenglandconsortium.org/)

Established in 1998, this consortium aims to disseminate information on IMDs to health care professionals across all levels involved in treating individuals with IMDs.⁴⁷ Its projects include acute illness materials for health care providers treating IMDs, including FAOD, UCD, OA, and MSUD. The materials cover the introduction, pathophysiology, clinical presentations, required assessments, diagnostic strategy, and treatment approaches for these conditions.

GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1116/)

It contains expert-authored, peer-reviewed online articles that describe specific inherited disorders.⁴⁸ Many IMDs are included with tables with acute metabolic decompensation in IMDs.

International Mito Patients (https://mitopatients.org/list-of-medicines/)

This group shares best practice, information, and knowledge on MitoD.⁴⁶ The website contains a list of medications that should be used with caution in MitoD.

OrphanAnaesthesia (https://www.orphananesthesia.eu/en/news.html)

This is an open-access database created in 2005 by the Scientific Working Group of Pediatric Anesthesia of the German Society of Anesthesiology and Intensive Care Medicine.⁴⁹ It provides peer-reviewed, freely available, and concise recommendations for anesthesiologists on how to plan and deliver anesthesia in patients with rare diseases, including IMDs.

Conclusion

This review highlights the importance of recognizing and managing IMDs in the setting of traumatic injuries and acute surgery. Raising awareness within trauma teams, along with a better understanding of the general principles of metabolic emergency management, is essential. Early recognition and timely intervention guided by a metabolic specialist and a coordinated, multidisciplinary approach are critical to optimizing outcomes for these patients.

Footnotes

ORCID iD

Yutaka Furuta

Ethical Considerations

The relevant institutional review board waived the need for ethical approval.

Author Contributions

Conception and study design: YF and JAP. Literature review: YF, RJT, and JAP. Drafting of the manuscript: YF and JAP. Critical revision: All authors critically reviewed and accepted the manuscript submitted.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Tiivoja

Reinson

Muru

, et al. The prevalence of inherited metabolic disorders in Estonian population over 30 years: a significant increase during study period. JIMD Rep. 2022;63(6):604-613. doi:10.1002/jmd2.12325

Sanderson

Green

Preece

Burton

. The incidence of inherited metabolic disorders in the west Midlands, UK. Arch Dis Child. 2006;91(11):896. doi:10.1136/adc.2005.091637; Epub 2006 May 11.

Furuta

Tinker

Hamid

, et al. A review of multiple diagnostic approaches in the undiagnosed diseases network to identify inherited metabolic diseases. Orphanet J Rare Dis. 2024;19(1):427. doi:10.1186/s13023-024-03423-3

Ferreira

Rahman

Keller

Zschocke

ICIMD Advisory Group . An international classification of inherited metabolic disorders (ICIMD). J Inherit Metab Dis. 2021;44(1):164-177. doi:10.1002/jimd.12348

Moio

Milke

Moutapam-Ngamby-Adriaansen

, et al. Diagnosis of inherited metabolic disease in older patients: a systematic literature review. J Inherit Metab Dis. 2025;48(3):e70038. doi:10.1002/jimd.70038

Ahrens-Nicklas

Slap

Ficicioglu

. Adolescent presentations of inborn errors of metabolism. J Adolesc Health. 2015;56(5):477-482. doi:10.1016/j.jadohealth.2015.01.008

Tarr

Morris

AAM

. Emergency management of intoxication-type inherited metabolic disorders. J Inherit Metab Dis. 2025;48(2):e70007. doi:10.1002/jimd.70007

Agana

Frueh

Kamboj

Patel

Kanungo

. Common metabolic disorder (inborn errors of metabolism) concerns in primary care practice. Ann Transl Med. 2018;6(24):469. doi:10.21037/atm.2018.12.34

Yeoh

Teng

Jackson

, et al. Metabolic disorders and anesthesia. Curr Anesthesiol Rep. 2019;9(3):340-359. doi:10.1007/s40140-019-00345-w; Epub 2019 Jul 12.

10.

Murphey

Krishna

. Inborn errors of metabolism and pregnancy. Am J Obstet Gynecol MFM. 2024;6(8):101399. doi:10.1016/j.ajogmf.2024.101399; Epub 2024 Jun 12.

11.

Wilcox

. Impact of pregnancy on inborn errors of metabolism. Rev Endocr Metab Disord. 2018;19(1):13-33. doi:10.1007/s11154-018-9455-2

12.

Machado

Pinheiro da Silva

. Hyperammonemia due to urea cycle disorders: a potentially fatal condition in the intensive care setting. J Intensive Care. 2014;2(1):22. doi:10.1186/2052-0492-2-22

13.

Stuart

Nargis

. Perioperative care of children with inherited metabolic disorders. Cont Educ Anaesth Crit Care Pain. 2010;11(2):62-68.

14.

Furuta

Tinker

Grochowsky

Phillips

3rd . The impact of ethnic and communication barriers on fatal metabolic emergent management of traumatic injury: a case report. Report. 2025;8(4):201. doi:10.3390/reports8040201

15.

Hasselgren

. Catabolic response to stress and injury: implications for regulation. World J Surg. 2000;24(12):1452-1459. doi:10.1007/s002680010262

16.

Hawkes

Walsh

O’Sullivan

Crushell

. Doctors’ knowledge of the acute management of inborn errors of metabolism. Acta Paediatr. 2011;100(3):461-463. doi:10.1111/j.1651-2227.2010.02062.x; Epub 2010 Nov 8.

17.

Solares

Heredia-Mena

Castelbón

, et al. Diagnosis and management of inborn errors of metabolism in adult patients in the emergency department. Diagnostics. 2021;11(11):2148. doi:10.3390/diagnostics11112148

18.

Forny

Hörster

Ballhausen

, et al. Guidelines for the diagnosis and management of methylmalonic acidaemia and propionic acidaemia: first revision. J Inherit Metab Dis. 2021;44(3):566-592. doi:10.1002/jimd.12370; Epub 2021 Mar 9. Erratum in: J Inherit Metab Dis. 2022 Jul;45(4):862. doi: 10.1002/jimd.12535.

19.

Baumgartner

Hörster

Dionisi-Vici

, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130. doi:10.1186/s13023-014-0130-8

20.

Alfadhel

Mutairi

Makhseed

, et al. Guidelines for acute management of hyperammonemia in the Middle East region. Therapeut Clin Risk Manag. 2016;12:479-487. doi:10.2147/TCRM.S93144

21.

Aldubayan

Rodan

Berry

Levy

. Acute illness protocol for fatty acid oxidation and carnitine disorders. Pediatr Emerg Care. 2017;33(4):296-301. doi:10.1097/PEC.0000000000001093

22.

Rodan

Aldubayan

Berry

Levy

. Acute illness protocol for urea cycle disorders. Pediatr Emerg Care. 2018;34(6):e115-e119. doi:10.1097/PEC.0000000000001298

23.

Aldubayan

Rodan

Berry

Levy

. Acute illness protocol for organic acidemias: methylmalonic acidemia and propionic acidemia. Pediatr Emerg Care. 2017;33(2):142-146. doi:10.1097/PEC.0000000000001028

24.

Rodan

Aldubayan

Berry

Levy

. Acute illness protocol for maple syrup urine disease. Pediatr Emerg Care. 2018;34(1):64-67. doi:10.1097/PEC.0000000000001299

25.

Häberle

Burlina

Chakrapani

, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision. J Inherit Metab Dis. 2019;42(6):1192-1230. doi:10.1002/jimd.12100; Epub 2019 May 15.

26.

Parikh

Saneto

Falk

, et al. A modern approach to the treatment of mitochondrial disease. Curr Treat Options Neurol. 2009;11(6):414-430. doi:10.1007/s11940-009-0046-0

27.

Parikh

Goldstein

Karaa

, et al. Patient care standards for primary mitochondrial disease: a consensus statement from the mitochondrial medicine society. Genet Med. 2017;19(12):1038/gim.2017.107.

28.

Buckley

Naim

Lynch

, et al. Sodium bicarbonate causes dose-dependent increases in cerebral blood flow in infants and children with single-ventricle physiology. Pediatr Res. 2013;73(5):668-673. doi:10.1038/pr.2013.25; Epub 2013 Feb 12.

29.

Yetimakman

Kesici

Tanyildiz

Bayrakci

. Continuous renal replacement therapy for treatment of severe attacks of inborn errors of metabolism. J Pediatr Intensive Care. 2019;8(3):164-169. doi:10.1055/s-0039-1683991; Epub 2019 Mar 27.

30.

Prietsch

Lindner

Zschocke

Nyhan

Hoffmann

. Emergency management of inherited metabolic diseases. J Inherit Metab Dis. 2002;25(7):531-546. doi:10.1023/a:1022040422590

31.

Kripps

Baker

2nd Thomas

, et al. REVIEW: practical strategies to maintain anabolism by intravenous nutritional management in children with inborn metabolic diseases. Mol Genet Metabol. 2021;133(3):231-241. doi:10.1016/j.ymgme.2021.04.007; Epub 2021 May 7.

32.

Kim

Sohn

. Anesthetic management of patients with carnitine deficiency or a defect of the fatty acid β-oxidation pathway: a narrative review. Medicine (Baltim). 2022;101(7):e28853. doi:10.1097/MD.0000000000028853

33.

Summar

. Current strategies for the management of neonatal urea cycle disorders. J Pediatr. 2001;138(1 Suppl):S30-S39. doi:10.1067/mpd.2001.111834

34.

Merritt

2nd MacLeod

Jurecka

Hainline

. Clinical manifestations and management of fatty acid oxidation disorders. Rev Endocr Metab Disord. 2020;21(4):479-493. doi:10.1007/s11154-020-09568-3

35.

Vockley

. Long-chain fatty acid oxidation disorders and current management strategies. Am J Manag Care. 2020;26(7 Suppl):S147-S154. doi:10.37765/ajmc.2020.88480

36.

Van Calcar

Sowa

Rohr

, et al. Nutrition management guideline for very-long chain acyl-CoA dehydrogenase deficiency (VLCAD): an evidence- and consensus-based approach. Mol Genet Metabol. 2020;131(1-2):23-37. doi:10.1016/j.ymgme.2020.10.001; Epub 2020 Oct 6.

37.

McGregor

Berry

Dipple

Hamid

Council on Genetics . Management principles for acute illness in patients with medium-chain acyl-coenzyme a dehydrogenase deficiency. Pediatrics. 2021;147(1):e2020040303. doi:10.1542/peds.2020-040303

38.

Longo

Frigeni

Pasquali

. Carnitine transport and fatty acid oxidation. Biochim Biophys Acta. 2016;1863(10):2422-2435. doi:10.1016/j.bbamcr.2016.01.023; Epub 2016 Jan 29.

39.

Singh

Rhead

Smith

Lee

Sniderman King

Summar

. Nutritional management of urea cycle disorders. Crit Care Clin. 2005;21(4 Suppl):S27-S35. doi:10.1016/j.ccc.2005.08.003

40.

Praphanphoj

Boyadjiev

Waber

Brusilow

Geraghty

. Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of acute hyperammonaemia. J Inherit Metab Dis. 2000;23(2):129-136. doi:10.1023/a:1005661631281

41.

Vockley

Ensenauer

. Isovaleric acidemia: new aspects of genetic and phenotypic heterogeneity. Am J Med Genet C Semin Med Genet. 2006;142C(2):95-103. doi:10.1002/ajmg.c.30089

42.

Häberle

Chakrapani

Ah Mew

Longo

. Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories. Orphanet J Rare Dis. 2018;13(1):219. doi:10.1186/s13023-018-0963-7

43.

Frazier

Allgeier

Homer

, et al. Nutrition management guideline for maple syrup urine disease: an evidence- and consensus-based approach. Mol Genet Metabol. 2014;112(3):210-217. doi:10.1016/j.ymgme.2014.05.006; Epub 2014 May 17.

44.

Strauss

Carson

Soltys

, et al. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): treatment, biomarkers, and outcomes. Mol Genet Metabol. 2020;129(3):193-206. doi:10.1016/j.ymgme.2020.01.006; Epub 2020 Jan 16.

45.

Rostampour

Dalili

Moravej

, et al. Comprehensive Iranian guidelines for the diagnosis and management of maple syrup urine disease: an evidence- and consensus-based approach. Orphanet J Rare Dis. 2025;20(1):8. doi:10.1186/s13023-025-03533-6

46.

New England consortium of metabolic programs. https://www.newenglandconsortium.org/

47.

GeneReviews. https://www.ncbi.nlm.nih.gov/books/NBK1116/

48.

International mito patients. https://mitopatients.org/list-of-medicines/

49.

OrphanAnaesthesia. https://www.orphananesthesia.eu/en/news.html

Emergency Management of Inherited Metabolic Disorders in Acute Surgical and Trauma Settings

Abstract

Keywords

Introduction

Trauma and Perioperative Considerations

Specific Scenarios

Fatty Acid Oxidation Disorders (FAODs)

Urea Cycle Disorders (UCDs)

Organic Acidemias (OAs)

Maple Syrup Urine Disorder (MSUD)

Mitochondrial Diseases (MitoD)

Useful Website Resources for Trauma and Surgical Providers

New England Consortium of Metabolic Programs (https://www.newenglandconsortium.org/)

GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1116/)

International Mito Patients (https://mitopatients.org/list-of-medicines/)

OrphanAnaesthesia (https://www.orphananesthesia.eu/en/news.html)

Conclusion

Footnotes

ORCID iD

Ethical Considerations

Author Contributions

Funding

Declaration of Conflicting Interests

References