The prevention of acute metabolic decompensations by timely recognition of catabolism, prompt safe treatment and communication is pivotal for IEM patients with fasting intolerance. This is the first study that describes safety and efficacy outcome measures of emergency protocols in IEM patients. We demonstrate that a generic emergency protocol can be safe and effective for home management by the caregivers and the first hour in-hospital management of metabolic emergencies in patients with hepatic GSD and MCADD. In the recent international liver GSD priority setting partnership, management of sickness and emergency situations was prioritized amongst the top 11 research priorities for liver GSD (23).
Interestingly, in our cohort relatively few patients were hypoglycemic at hospital admission. Hypoglycemia was uncommon in ketotic GSD patients and verbal FAOD patients. This is remarkable because an important subset of the IEM patients has severe fasting intolerance with regular hypoglycemias in daily life (24). Importantly, the objective of our study justified a relatively conservative hypoglycemia definition of < 3.9 mmol/L, rather than 2.6 mmol/L as used in other studies (25). The preventive character of our emergency protocol and the relatively high initial carbohydrate intake -estimated based on the actual body weight (20)- aim to prevent catabolism to a maximum extent and to promptly reach out for further medical treatment, if needed. This approach likely has prevented hypoglycemias in many IEM patients with severe fasting intolerance.
Convulsions, coma, or death were not reported in the present cohort of 128 patients in the past 5 years. Nonetheless, hospital admissions were frequent among all studied IEMs. Although, newborn screening for FAOD has led to a significant reduction in deaths and serious adverse events (24), acute care utilization remains high in these patients compared to age-matched controls. In line with our study, a retrospective cohort study in patients with IEMs identified through newborn screening between 2006–2007 reported that 44% (27 out of 61) of patients with a FAOD had IEM-related acute care utilization during their first year of life (26). Another recent study from Canada reported that children with MCADD experienced on average 0.6 hospital admissions per year, from six to 12 months of age (27). Long-term data on hospital admissions in patients diagnosed with hepatic GSD is lacking, but results from an international questionnaire showed that hospital admission due to complications of dietary management are common (24). In the latter study, 61% of the respondents reported using a written emergency protocol. Nevertheless, it remains speculative how the implementation of emergency protocol affects acute care utilization in patients with IEM associated with fasting intolerance.
The recognition of catabolism and metabolic decompensation in patients with IEM is challenged by IEM-specific pathophysiology of fasting. For instance, in GSDI patients lactate can function as alternative energy substrate to glucose for the brain (28). As a consequence, patients may remain without clear neuroglycopenia related symptoms during hypoglycemia. In patients with FAOD, however, hypoglycemia is a relatively late finding of metabolic decompensation and often preceded by lethargy and vomiting (29). Indeed, in the present study we found that lethargy was reported in three out of four MCADD patients in whom glucose concentrations were above hypoglycemic cutoff values. Therefore, although our protocol is generic, caregivers and patients instructions should be individualized, and education and clinical pathways are both crucial to optimize emergency care of IEM patients (30,31).
Potential weakness of this study is the retrospective design introducing selection bias and information bias. There is lack of interoperability and interconnectivity between different EHR systems. Hospital admissions and initial laboratory studies may not always have been communicated with our center or documented in the EHR system. However, it is unlikely that we have missed metabolic decompensations causing death, coma, convulsions and/or ICU admissions. In this study, we were not able to include a control group, theoretically IEM-specific emergency letters may be as effective. Furthermore, it is unknown how many hospital admissions have been prevented by starting phase I of the emergency protocol at home, and if the emergency solution was well tolerated. Finally, the number of patients included in this study with a FAOD other than MCADD was low, and safety and efficacy of generic emergency protocols for patients with IEMs of the intoxication type needs to be assessed. However, as prevention of catabolism is also key in intoxication type of inborn errors of metabolism, the generic emergency protocol with use of the carbohydrate solution can be used as well, with addition of disease specific remarks. Obviously, our generic emergency protocols are contraindicated in patients with a ketogenic or carbohydrate restricted diet.
The emergency letters are part of a shared care model, which uses the medical and communication competences of all stakeholders; the metabolic center of expertise, the local healthcare providers, the caregivers and the patients, who all share joint responsibility. We have recently digitalized our emergency protocol as part of the GSD Communication Platform; a telemedicine platform for patients with hepatic GSD (32). Future perspectives may include next digitalization steps to support national and international interconnectivity between EHR systems of different healthcare professionals, including rare disease registries and the European Reference Networks for Rare Hereditary Metabolic Disorders (33).