Initiation of KD in SRSE in critical care settings is often associated with significant challenges including multiple intravenous infusions, difficulty in eliminating all sources of carbohydrates, use of corticosteroids which can inhibit the establishment of ketosis, inability to provide enteral nutrition, and lack of a skilled team with expertise in KD formulation and implementation. As these challenges involve multidisciplinary issues, a trained collaborative team composed of neurologists/epileptologists, intensivists, dietitians, pharmacists, and nurses is important and should be involved throughout the course of KD implementation in critical care settings [13, 15, 19, 34].
At present, despite the lack of validated guidelines, considerable experience in practice has been accumulated. The International Ketogenic Diet Study Group has given detailed recommendations on various aspects of KD use in the treatment of epilepsy in children. Most of them are also applicable in KD treatment for SRSE [9]. Some clinical studies have reported practical approaches which seem to work well in their respective centers [13, 14, 19, 35, 48, 54]. Here, we propose a protocol to implement KD for SRSE in ICUs based on the current reviews and clinical practice (Fig. 1).
Pre-diet evaluation
After ruling out contraindications, a pre-diet evaluation is recommended before KD initiation. By measuring the height and weight, the basic nutritional status is evaluated and the required calories and fluid are estimated. To help evaluate the seizure type, nutritional status and complications, we recommend the following laboratory and ancillary examinations, by combining the experience of other centers [9, 13, 14, 19, 35, 48, 54]: complete blood count, fasting lipid profile, electrolyte and trace elements (including calcium, phosphorus, iron, magnesium, zinc, selenium), serum liver and kidney tests, blood gas analysis (including serum bicarbonate), serum acylcarnitine profile, vitamin D level, urinalysis (including urine ketones), and electroencephalogram (EEG). If applicable and conditions permit, continuous EEG monitoring, abdominal and urinary ultrasound, ECG and echocardiography (strongly needed in the presence of a history of heart disease), bone age (for children) and bone mineral density, amylase and lipase (for parenteral KD) test are advised.
Recommendations
The recommended pre-diet evaluation includes baseline weight and height; complete blood count, fasting lipid profile, electrolyte and trace elements, serum liver and kidney tests, blood gas analysis, serum acylcarnitine profile, vitamin D level, urinalysis, and EEG. Optional examinations include continuous EEG monitoring, abdominal and urinary ultrasound, ECG and echocardiography, bone age and bone mineral density, amylase and lipase test.
Diet initiation and maintenance
Feeding methods
Due to the anesthetic-induced coma therapy, most of the patients with SRSE are enterally fed via a gastrostomy or a nasogastric tube. In this condition, KD may be provided as an all-liquid, formula-based diet. Liquid diets may be appropriate as enteral delivery has good patient compliance and high efficacy [55, 56]. There is a variety of commercial formula products available. Although all products are fortified with vitamins and minerals, the diet therapy should be supplemented to meet the Dietary Reference Intakes (DRIs) [57, 58].
In ICUs, because of the critical status of the patients who are often in a coma or unable to tolerate enteral feeds (due to, e.g., ileus and intestinal failure), sometimes KD therapy needs to be started through parenteral administration, which usually acts as a temporary bridge towards enteral KD [59].
The preparation of parenteral KD could be feasible with commercially available, standard intravenous fat and amino acid solutions [60, 61]. For example, a parenteral KD preparation can contain commercially available fat emulsion with medium-chain triglycerides (20% lipid emulsion), fat emulsion with long-chain triglyceride (20% lipid emulsion), and amino acid hyperalimentation (6.67% or 10% concentration). Glucose-free solutions such as saline can also be contained as required. Ketogenic parenteral nutrition can be prepared by properly combining these solutions. The Ketogenic parenteral nutrition is mixed in a laminar air flow under sterile conditions and administered to the patient via a central or a peripheral line [62]. It can be infused continuously over 16 h and stopped for 8 h at nighttime.
Intravenous KD may increase the risk of transient elevation of liver enzymes, lipid profiles, and pancreatic enzyme concentrations. Additionally, patients with SRSE are often receiving multiple medications that are metabolized in the liver. Intravenous KD may enhance cholestasis and hepatotoxicity [33, 60]. Farias-Moeller et al. once reported a 5-year-old child who experienced severe pancreatitis while being on the combinational treatment of valproic acid and intravenous KD [19]. Therefore, enteral KD is preferred if the patient condition permits, and rigorous monitoring of lipids and pancreatic enzymes in patients receiving parenteral KD is required. As soon as the patient can absorb nutrients through the digestive tract, intravenous KD should be switched to enteral or oral administration.
Recommendations
Enteral KD is preferred if the patient condition permits. Parenteral KD may benefit patients with enteral feeding intolerance. Ketogenic parenteral nutrition can be prepared with commercially available fat and amino acid solutions. Intravenous administration of KD should be switched to enteral or oral approach once the patient can absorb nutrients through the digestive tract.
Classic KD
The determination of diet regimen requires professional help from dietitians. According to the available reports, the majority of patients with RSE/SRSE follow the classic KD. Almost all adults and 83% (74/89) of children are given a target ketogenic ratio (fat to protein plus carbohydrates) of 4:1 [12, 21, 24]. Till now, the efficacy of different ketogenic ratios for SRSE has not been specially compared because of the rarity of the disease. As patient compliance to KD is usually not an issue in patients with RSE/SRSE due to their critical condition, KD can be started or rapidly escalated to the 4:1 ratio [12, 23]. This aggressive administration helps to produce ketosis quickly and effectively. On the other hand, some studies have reported the use of a stepwise approach, which initiates KD at a low ratio and then gradually advances to the ratio of 3–4:1. This approach shows comparable efficacy in suppressing SE, but may lead to delayed ketosis [18, 35, 63].
As ketone bodies are considered to have an antiepileptogenic effect, one of the goals of KD therapy is to achieve ketosis [10]. Successful KD initiation marked by achievement of ketosis is feasible in the ICUs, and in literature, 96% of children could achieve ketosis [21]. Regarding the optional levels of ketosis, current data from literature are insufficient. In addition, a consistent ketosis level may not be easy to maintain in the ICUs partly due to the complicated concomitant medications such as corticosteroids, barbiturates, anesthetics, and carbohydrate-containing medications. The common presence of carbohydrates in medications and intravenous fluids can interfere with the production of ketone bodies. Minimizing carbohydrates in medications and fluids is therefore essential for the onset and maintenance of ketosis. The limitation of carbohydrates of medical origin should be assisted by pharmacists, and a well-designed treatment protocol can help achieve ketosis more efficiently. In two studies with standardized KD treatment protocols, ketosis was achieved in 25 out of 26 (96%) adult patients with RSE/SRSE, and the median time to achieve ketosis was 1–2 days. In contrast, in earlier case reports, the time to achieve ketosis was at least 3.5 days in adults with RSE/SRSE [24].
The traditional method of initiating KD involves a period of fasting (12–24 h), with no carbohydrate-containing fluids provided. Fasting may lead to a quicker ketosis and seizure reduction, and therefore is advantageous for SRSE where a more immediate response is desired [64, 65]. However, fasting is by no means mandatory. Since it may lead to additional adverse events such as hypoglycemia and acidosis, fasting should be considered on an individual basis. If fasting is applied, glycemia and serum bicarbonate should be monitored frequently [9, 66]. Yet in the current literature, a compromised approach has been successfully applied in SRSE patients in some centers, which includes a 1/3 or 1/2 cal for the first 24 h, followed by advancement in every 1–3 days by 1/3 or 1/2 caloric intervals until full calories [13, 14, 18, 50]. This approach seems to offer a good balance between efficacy and side effects. For infants, it is more appropriate to initiate KD with a low ketogenic ratio (e.g., 1:1 or 2:1) and then gradually advance and titrate the ratio [50, 67, 68].
Recommendations
Classic KD with a 4:1 ratio is recommended. If there is no patient compliance issue, KD initiation with this high ratio directly is usually feasible and effective. And the ratio can also be individualized on a case-by-case basis and adjusted as needed. For example, it is suggested that KD start with a lower ketogenic ratio and/or a lower portion of energy needs, and then advance it to the goal ratio and/or full calories. Fasting is optional when a more rapid KD benefit is desired.
Alternative KD types
Less restrictive types of KD, such as the modified Atkins diet (MAD) and the low glycemic index treatment (LGIT), have also been successfully used to treat patients with nonconvulsive SE [30, 69]. Numerous studies on intractable epilepsy have shown that compared with the classic KD, MAD and LGIT have advantage of better tolerability [70]. However, clinical experience on these KD variants for SRSE treatment is too little to make a conclusion. For patients with SRSE, compliance problems rarely occur in the acute phase; instead, they may arise when patients begin to eat orally. In this case, a switch from classic KD to MAD or LGIT can be considered, especially for adolescents and adults.
Recommendations
When compliance issues arise from the start of oral feeding or when patients intend to continue KD in the long term, alternative KD such as MAD and LGIT can be considered, especially for teenagers and adults.
Supplementation
For non-full nutritional formula, carbohydrate-free multivitamin, minerals, vitamin D and calcium should be supplied to meet the recommended daily nutritional requirements. Although commercial formula-based KD products are usually fortified with vitamins and minerals, supplementations are sometimes still needed according to DRIs. And age-appropriate requirements should be considered [9, 71, 72]. Oral citrates can reduce the risk of metabolic acidosis and kidney stones in children treated with KD [9, 73]. They can be supplemented in patients receiving enteral or oral nutrition. Carnitine supplementation has been a controversial issue. Empiric carnitine supplementation can be expensive and adds an additional medication to patients. Most ketogenic centers recommend carnitine supplementation if it is at a low level or when patients become symptomatic [9, 74].
Recommendations
Multivitamin, minerals, vitamin D, calcium, citrates, and carnitine can be supplemented according to patients’ condition.
Monitoring and adverse events
First, monitoring of vital signs, including continuous ECG, is required. This is usually the default setting in ICUs. Second, once KD is initiated, serum glucose (e.g., q4h, and then q8h after ketosis), serum β-hydroxybutyrate (e.g., q24h) and urine ketones (e.g., q12h-q24h) should be monitored to assess the ketosis status[9, 13, 14, 19, 34]. Ketosis can be defined as > 3 mmol/L serum β-hydroxybutyrate, or > 3 + urine ketones [13, 21]. The serum ketosis is more accurate, but it is more expensive and requires finger sticks. We recommend that both indicators be monitored during KD implementation [75]. Third, assessments including complete blood count, fasting lipid profile, electrolyte, serum liver and kidney tests, blood gas analysis, and urinalysis should be appropriately re-examined to detect adverse events and complications. The adverse events/complications requiring interventions include metabolic acidosis defined as serum CO2 < 16 mmol/L and hypoglycemia defined as serum glucose < 2.2 mmol/L, for which interventions include bicarbonate and sugar supplementation, respectively. Fourth, EEG should be re-examined in a timely manner to assess the epileptic electrical activity. In institutions where conditions permit, continuous EEG monitoring is strongly recommended. Lastly, during a long KD therapy, weight and height should be measured weekly and urinary ultrasound, bone mineral density, and vitamin D level should be re-examined regularly to reassess the nutritional status and detect long-term adverse events/complications [9].
KD is generally safe in RSE/SRSE cohorts. Adverse events have been reported in about 1/3–1/2 of the patients with RSE/SRSE [12, 21]. Commonly reported adverse events are similar in children and adults, including gastrointestinal disturbance (e.g., regurgitation, vomiting, constipation, diarrhea, abdominal distention, and gastrointestinal paresis), hyperlipidemia, acidosis, and hypoglycemia. Other less common side effects include elevated liver enzymes, hypokalemia, hyponatremia, hypoproteinemia, weight loss, kidney stones, pancreatitis, and arrhythmia. KD should be stopped when serious adverse events occur, such as fatal arrhythmia (ventricular fibrillation) and pancreatitis [12, 21, 76]. Some serious complications such as sepsis and aspiration pneumonia have also been reported, which, however, are not necessarily attributable to KD. The majority of the adverse events could be successfully managed with symptomatic and supportive treatment and do not necessitate KD discontinuation [12, 15, 21]. Still, close monitoring and preventive management of potential adverse events are important for successful KD treatment.
Recommendations
After KD initiation, it is recommended to closely monitor serum glucose, serum β-hydroxybutyrate and urine ketones, and timely re-examine the complete blood count, fasting lipid profile, electrolyte, serum liver and kidney tests, blood gas analysis, and urinalysis. Regular EEG or continuous EEG monitoring is key to the evaluation of therapeutic effect. During a long KD therapy, weekly measurement of weight and height and regular examination of urinary ultrasound, bone mineral density, and vitamin D level are recommended. The most common adverse events are gastrointestinal symptoms, hyperlipidemia, acidosis, and hypoglycemia. Most of the patients can well tolerate the diet without serious adverse events. Close monitoring and preventive management of potential adverse events are important.