We retrospectively identified data collected prospectively from patients who were admitted to our intensive care unit (ICU) and underwent coma therapy, or TTM, for more than 72 hours from March 2019 to May 2022. Patients with oliguria or chronic kidney disease making urine collection challenging, as well as those lacking sufficient data for each treatment phase established in the study, were excluded.

Baseline characteristics, including age, sex, initial body weight and height, and medical history (e.g., diabetes mellitus, hypertension, dyslipidemia, heart disease, stroke, and cancer), were evaluated. In addition, we obtained clinical information regarding the initial Glasgow coma scale (GCS), length of stay in the ICU, starting time and ending time of TTM, and coma therapy.

We analyzed protein requirements using UUN measurements from urine collected via a Foley catheter over a 24-hour period. During the treatment application and maintenance phases, one test was conducted, and an additional test was performed during the tapering phase after achieving the treatment goals. We divided the entire treatment period into two groups, namely phase 1 and phase 2, for comparison. Phase 1 was defined as the period from the initiation of coma therapy and TTM until just before tapering, while phase 2 was defined as the period from the start of tapering until the discontinuation of coma therapy and TTM. According to Bingham [4], the patient’s ‘protein requirement’ was defined as the protein mass needed to achieve a nitrogen balance within ±5 [4]. In this study, we adopted the same approach to calculate the patient’s protein requirement. The formula used for the calculation is as follows : nitrogen balance (g/day) = protein intake (g) / 6.25 - (UUN + 4).

We compared the protein requirement for each phase using the Wilcoxon rank-sum test and performed the Dun’s test for post hoc analyses. The same methods were used for subgroup analyses by diagnoses. All statistical analyses were performed using R software (The R Foundation, Vienna, Austria).

Data from 195 patients was collected between March 2019 and May 2022. Out of these, 88 patients who met the exclusion criteria were excluded, including three with renal impairment and 85 with insufficient UUN data for each phase. Ultimately, a total of 214 UUN data points from 107 patients were utilized for the analyses.

Among the patients, 44.9% were male (n=48), and the mean age was 56.6±17.8 years. Twenty-five patients (23.4%) had a history of diabetes mellitus, 34 (31.8%) had hypertension, 11 (10.3%) had heart disease, and 15 (14.0%) had a history of stroke. Twelve patients (11.2%) had a history of cancer.

Regarding the specific diagnoses, 28 patients (26.7%) were diagnosed with subarachnoid hemorrhage (SAH), 27 (25.7%) with intracerebral hemorrhage (ICH), 22 (21.0%) with brain tumor, 18 (17.1%) with TBI, five (4.8%) with ischemic stroke, and three (2.9%) with pure intraventricular hemorrhage. The median initial GCS score was 9 (range, 6-14), and the modified Rankin scale score was 4 (range, 3-5). The mean length of stay in the ICU was 19.5±13.9 days (Table 1).

Out of the total 214 UUN data collected from 107 patients, the mean value of protein requirements, as measured by UUN throughout the entire period, was 1.84±0.62 g/kg/day. During phase 1, the protein requirement was 1.49±0.42 g/kg/day, while in phase 2, as the treatment was tapered, it increased to 2.18±0.60 g/kg/day. This increase demonstrates statistical significance (p<0.0001, Fig. 1).

In the subgroup analyses based on specific diagnoses, consistent findings were observed. For patients diagnosed with SAH, the protein requirement during phase 1 was 1.39±0.31 g/kg/day, which increased to 2.16±0.55 g/kg/day during phase 2. Similarly, in patients with ICH, the protein requirement was 1.56±0.49 g/kg/day in phase 1 and increased to 2.32±0.80 g/kg/day in phase 2. Patients with brain tumors demonstrated a protein requirement of 1.62±0.54 g/kg/day in phase 1, rising to 2.17±0.49 g/kg/day in phase 2. Likewise, those with TBI exhibited a protein requirement of 1.42±0.27 g/kg/day in phase 1 and 2.14±0.48 g/kg/day in phase 2. In all subgroups, a significant increase was observed between phases, demonstrating the clinical relevance of these findings (Fig. 2).

Protein is the essential macronutrient for wound healing, immune function, and maintaining body mass in critically ill patients, and thus is more than just a source of calories [19]. Compher and colleagues [8] showed that the odds of death decreased by 6.6% with each 10% increase in protein intake. Furthermore, adequate protein intake was also found to help reduce the time to wean from the ventilator and shorten the length of stay in the ICU [16]. A lot of guidelines emphasize protein intake, recognizing its significance beyond providing calories. According to the 2016 ASPEN guidelines, critically ill patients require 1.2 to 2.0 g/kg of protein per day, with higher protein intake recommended for severe stress situations such as burns and multiple fractures [19]. Specifically, for TBI, the guideline suggests a protein intake as high as 1.5-2.5 g/kg/day, which aligns with our findings. The 2019 ESPEN guideline also recommends supplying at least 1.3 g/kg of protein daily to critically ill patients [25].

In general, critically ill patients are likely to fall into a catalytic state in the acute phase, so the demand for systemic and protein metabolism increases [11]. However, some reports showed that patients receive only 25-60% of their protein requirements on average during intensive care, which was also associated with a poor prognosis [28]. While neurocritical patients have more stress factors than other critical patients, it has been confirmed that they experience negative nitrogen balance and protein shortage problems [2,3,7,15,27].

Since the brain is a high-nutrient-metabolic organ that uses 20% of TEE, changes in brain metabolism can also lead to changes in the patient’s TEE. This is related not only to protein catabolism caused by the systemic inflammatory response along with brain damage but also to the intensity level of treatment applied [3,15,27]. Neurocritical treatments, such as coma therapy, deep sedation, or TTM, lower the brain metabolism rate and decrease ICP. Previous studies have shown that the resting metabolic rate is reduced by 25% when propofol sedation is applied [9,21]. Body temperature is also a factor that affects energy consumption. It is known that the cerebral metabolic rate decreases by 5% to 7% and energy consumption by 10% to 13% with every drop of a degree Celsius in the body temperature [10,18]. Coma therapy is also known to reduce systemic metabolism and body temperature [13]. Nevertheless, limited research has been conducted regarding the impact of these therapies on protein metabolism. Through the ICP-guided treatment, we successfully maintained ICP and optimal cerebral perfusion pressure in most patients included in our study. Despite the adequate utilization of coma therapy and TTM, the protein requirements identified in our study (1.50±0.44 g/kg/day) fell within the upper range of the preexisting guideline, as suggested by ASPEN. These requirements would have been higher if coma therapy or TTM were not applied. Consequently, if nutrition supply is planned based on the overall reduced calorie requirements, it becomes difficult to supply sufficient protein. Buckley and Dickerson [6] also highlighted that patients may be at risk of protein deficiency during propofol sedation.

Considering the impact of protein on neurological patients, it is essential to probe protein requirements with regard to brain metabolism. In our study, a significant increase in protein requirements was observed between phases 1 and 2. Therefore, it would be more advisable to monitor protein requirements at each treatment phase than at regular intervals. By measuring protein requirements and supplying an adequate amount, we can minimize protein shortages. Furthermore, while the overall caloric demand diminishes due to the effects of interventions such as coma therapy and TTM, the protein requirement during phase 1 remains notably high (1.49±0.42). Given this, it becomes necessary to contemplate how to incorporate these findings into the patient’s nutritional plan. Of course, research on functional outcomes should precede this.

First, as a retrospective study, it is crucial to acknowledge that this research is inherently constrained by some missing data. Second, conducting a comprehensive analysis of factors that might influence UUN, such as blood transfusions, vasopressor usage, and patients’ digestive capacity, was challenging due to methodological complexities. Third, in the cases of relatively mild patients who did not undergo coma therapy and TTM in neurocritical care or non-neurocritical patients, we did not perform early and thorough UUN analysis, so there were no control groups to confirm the increased protein requirement and its changes. Fourth, we did not observe an association between protein supplementation using UUN and clinical outcomes. Nevertheless, this study lays the groundwork for future investigations that explore the potential benefits of tailoring protein supplementation based on individual patients’ specific protein requirements to enhance their clinical outcomes.