Investigating the differences in nutritional status between successfully weaned and unsuccessfully weaned respirator patients

Long-term respirator users admitted to intensive care units need to be transferred to a respiratory care center (RCC) for weaning. It may cause malnutrition in critical care patients, which may manifest as a reduction in respiratory muscle mass, lower ventilatory capacity, and decreased respiratory tolerance. This study aimed to assess that if the patients’ nutritional status were improved, it could help RCC patients to wean from respirators. All participants were recruited from the RCC of a medical foundation in the city and Taipei Tzu Chi Hospital. The indicators include serum albumin level, respirator detachment index, maximum inspiratory pressure (PImax), rapid shallow breathing index, and body composition measurements. We recorded the length of hospital stay, mortality, and RCW (respiratory care ward) referral rate for these participants and analyzed the differences in relevant research indicators between those who were and weren’t weaned off. 43 of 62 patients were weaned from respirators, while 19 failed. The resuscitation rate was 54.8%. Patients with respirator weaning had a lower number of RCC admission days (23.1 ± 11.1 days) than respirator-dependent patients (35.6 ± 7.8 days, P < 0.05). The PImax of successfully weaned patients had a greater reduction (− 27.09 ± 9.7 cmH2O) than unsuccessful ones (− 21.4 ± 10.2 cmH2O, P < 0.05). The Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of successfully weaned patients (15.8 ± 5.0) were lower than those who were not (20.4 ± 8.4, P < 0.05). There was no significant difference in serum albumin levels between the two groups. In the successfully weaned patients, the serum albumin concentration was increased from 2.2 ± 0.3 to 2.5 ± 0.4 mg/dL, P < 0.05. Improved nutritional status can help RCC patients to wean from respirators.


Methods
Research methods. This study had a prospective research design. All participants were recruited from a hospital respiratory care center (RCC) and a medical foundation in the city. All patients were over 18 years old and needed to use respirators. The exclusion criteria were a fraction of inspired oxygen > 0.6%, air leaks through chest drains, severe liver disease (Child-Pugh score C), and combined Chinese medicine and acupuncture treatment. Even if the patients with respiratory infection using antibiotic therapy, they could still be part of the study since we were like to observed the whole process of successfully weaned or not. All methods were performed in accordance with relevant guidelines and regulations. The informed consent was obtained from all participants and/or their legal guardians. All experimental protocols were approved by the Buddhist Tzu Chi Medical Foundation Taipei Tzu Chi Hospital Institutional Review Board.
Research indicators and tools. The indicators used in this study included body position measurement, serum albumin level, respirator detachment index (weaning index), and body composition measurements.
In the body position measurement aspect, the WHO formula body calculation was used: BMI = (body weight [kg])/(height [m]) 2 .
The Executive Yuan Department of Health standard for BMI was adopted (light obesity: 27 ≤ BMI < 30, moderate obesity: 30 ≤ BMI < 35, and severe obesity: BMI ≥ 35), but because the patients could not stand, body weight was measured using a bed scale (DETECTO, Missouri/USA), and height was estimated by the knee height using the formula proposed by Cheng et al. 21 . Knee height was measured with the femur and tibia perpendicular to each other and the bottom of the foot perpendicular to the tibia. The length from the joint to the sole was defined as knee height and used in the following height estimation formula: 1. Male: Length (cm) = 85.10 + 1.73 × knee height (cm)-0.11 × age (years) 2. Women: Length (cm) = 91.45 + 1.53 × knee height (cm)-0.16 × age (years).
PImax and RSBI were used as indicators for respirator detachment. PImax was measured by an inspforce (BUEHRINGER, USA), and RSBI was measured using a Haloscale Wright Respirometer (FERRARIS, Germany). Body composition was analyzed using a bio-resistance body composition analyzer (InBody S10, Biospace, Korea) to estimate the participants' fat-free weight, body fat mass, muscle mass, mineral (bone), total body water, protein, intracellular fluid, and extracellular fluid contents. The time of the baseline and the follow-up data would be measured before we gave them the commercial formula that day and for those who still rely on the respirator while others were measured when they successfully weaned. www.nature.com/scientificreports/ Research process. Family members of patients who were interested in participating in this study could only sign up the patients for participation after they had listened to the researcher's explanation, fully understood the content of the study, and signed a consent form. When participants entered the study, and when they left RCC, the researchers collected data, including basic data, disease history, medication status, blood biochemical test data, diet data, and body composition data. The diet was commercial formula for the tube feeding products and supplied them based on each patients' body weight. The researchers also collected information on the length of hospital stay, mortality, and RCW referral rate for these participants and analyzed the differences in relevant research indicators between those who were weaned off the respirator and those who were not.

Results
A total of 86 RCC patients were included in this study. Among them, 22 patients from respiratory care centers were discharged or transferred after signing the consent form, one patient had a cardiac pacemaker, and one had finger necrosis that precluded measurement of they were excluded. All of 62 RCC patients were included in the data analysis, of whom 43 were successfully weaned off the ventilator, 11 were transferred to RCW, and 8 were transferred to ICU or died.

Patients' characteristics.
Analysis of the basic data of the patients. All 62 RCC patients were grouped according to whether they were successfully weaned. Their mean age (± standard deviation) was 73.7 ± 16.0 years, of whom 35 (56.5%) were male, and 27 (43.5%) were female (Table 1). Of the 62 patients, 39 (62.9%) and 23 (37.1%) were from the medical intensive care unit (MICU) and surgical intensive care unit (SICU), respectively. In the successful weaning group, 23 (37.1%) and 20 (32.3%) were from the medical intensive care unit (MICU) and surgical intensive care unit (SICU), respectively. In the unsuccessful weaning group, 16 (25.8%) and 3 (4.8%) were from the medical intensive care unit (MICU) and surgical intensive care unit (SICU), respectively ( Table 1). The success rate of ventilator weaning was significantly higher in the medical intensive care unit (MICU) than in the surgical intensive care unit (SICU) (p < 0.05) ( Table 1).
Analyzing disease severity, the mean APACHE II score for the 62 patients was 20.0 ± 4.5. The mean APACHE II score of the 43 patients in the successful weaning group was 19.2 ± 3.9 points, which was significantly lower than the mean APACHE II score of 21.7 ± 5.3 points in the 19 patients in the other group (p < 0.05). (Table 1).
Analysis of dietary intake data. The mean daily caloric and protein intake of the 62 patients were 1683.8 ± 227.0 kcal and 79.1 ± 19.5 g. Among them, the average daily calorie and protein intake of 43 patients in the successful weaning group were 1722.1 ± 240.6 kcal and 82.8 ± 20.9 g, significantly higher than the average daily intake of 19 patients in the unsuccessful weaning group. As a result, the average daily caloric intake and protein intake were 1597.4 ± 167.9 kcal and 70.8 ± 13.2 g (p < 0.05) ( Table 2). www.nature.com/scientificreports/ Analysis of respirator disengagement metrics. The average RSBI was 93.5 ± 41.3 bpm/L when the 62 patients entered the respiratory care center (RCC). Among them, the average RSBI of 43 patients in the successful weaning group was 89.8 ± 42.7 bpm/L when they entered the RCC; the average RSBI value of the 19 patients in the unsuccessful weaning group was 101.8 when they entered the RCC. ± 37.9 bpm/L. The results showed that although the patients in the successful weaning group entered the RCC, the average RSBI value of the patients all tended to be lower than the average RSBI value of the patients in the unsuccessful weaning group, but there was no significant statistical difference (Table 1). Analyzing the PImax, the mean of the 62 patients entering the RCC was − 26.6 ± 10.9 cmH 2 O. Among them, the average of 43 patients in the successful weaning group was − 27.3 ± 11.9 cmH 2 O when entering the RCC; the average value of the 19 patients in the unsuccessful weaning group was − 25.1 ± 8.5 cmH 2 O when entering the RCC, There was no statistically significant difference between the two groups ( Table 2). Table 3, the results of univariate Logistic regression analysis, "Transfer in" (OR = 4.64, p = 0.028), "Energy" (OR = 1.00, p = 0.046), "Protein" (OR = 1.05, p = 0.034), "Group of formula" (OR = 3.40, p = 0.039), "Sex" (OR = 4.49, p = 0.011), "Respirator days" (OR = 0.84, p < 0.001), "Albumin" (OR = 0.25, p = 0.018) and "Height" (OR = 1.08, p = 0.042) reaches the significant level in the regression coefficient (p < 0.05) which indicates that these independent variables are significantly associated with the likelihood of successful respirator disengagement. Therefore, multivariate Logistic regression was used as an independent variable for analysis.

Analyze body composition analysis and muscle mass distribution. In
The results of final multivariate Logistic regression analysis showed that only the regression coefficient of "Respirator days" (OR = 0.78, p = 0.002) reached a significant level (p < 0.05), and its OR value was lower than 1, indicating that the case the more days the respirator is used, the lower the probability of successful disengagement of the respirator; in addition, the significance of some variables is quite close to 0.05, including "protein" (OR = 1.06, p = 0.080). Its OR value is higher than 1, which means that the higher the protein intake of the case, the higher the probability of successful escape from the respirator.
Analysis of patient's blood serum albumin. The mean serum albumin concentration in the 62 patients was 2.3 ± 0.3 g/dL. Among them, the mean serum albumin concentration of 43 patients in the successful weaning group was 2.2 ± 0.3 g/dL, which was significantly lower than the mean serum albumin concentration of the 19 patients in the unsuccessful weaning group of 2.4 ± 0.3 g/dL (p < 0.05) ( Table 3).  www.nature.com/scientificreports/ albumin by intravenous injection. The results showed that in the successful weaning group, significantly more patients did not receive serum albumin supplementation by intravenous injection (p < 0.05) ( Table 3).

Discussion
Calorie and protein intake and the patient's respirator detachment. Insufficient nutrition will lead to muscle loss, and excessive nutrition will increase the need for ventilation. Both lead to weakness of the respiratory muscles, resulting in respiratory failure and failure of respirator weaning. Therefore, providing proper nutrition for patients who use respirators for a long time can help maintain good nutritional status and aid in weaning from respirators. According to the results of this study, the successful weaning group had a higher average daily calorie and protein intake (successful weaning group: 1722.1 ± 240.6 kcal and 82.8 ± 20.9 g, unsuccessful weaning group: 1597.4 ± 167.9 kcal and 70.8 ± 13.2 g, respectively; P < 0.05) ( Table 3).
Cerra et al. 22 believed that when a patient is in a chronic severe disease stage, the target calorie intake should be 18-25 kcal/kgBW/day. Doley et al. 23 suggested that a chronically severely ill patient on prolonged respirator use should be given at least 20-30 kcal/kgBW/day. The ASPEN guidelines suggest that when there is no means of performing "indirect calorimetry," the calorie needs of critically ill patients can be calculated using commonly used evaluation formulas or should be 25-30 kcal/kgBW/d; the recommended amount of protein is 1.2-2.0 g/ kgBW/d. Therefore, all participants in this study met the recommended daily calorie intake standards.
In terms of protein intake, the average amount of protein per kilogram of body weight given to the successful weaning group was 1.4 ± 0.3 g/kg, which is close to that reported by Lin et al. in their study 24 . However, according to the 24-h urine urea nitrogen (UUN) test findings and clinical conditions, it was adjusted to 1.57 ± 0.4 g/kg.
Lin et al. 24 studied the effects of factors such as protein metabolism and nutritional status on respirator detachment in 156 patients in an RCC. Most patients were elderly individuals over 70 years (57.1%), and 42.7% were men. The results showed that before a patient was transferred to an RCC, his dietary protein intake was 1.135 ± 0.33 g/kg/day. It was increased to 1.57 ± 0.422 g/kg/day during the study period based on UUN test findings and clinical conditions. The balance increased from − 3.552 ± 4.4 to − 0.4485 ± 3.62, and RSBI decreased from 73.73 ± 59.54 to 49.5 ± 61.15. In this study the results of the successful escape from the respirator group before entering RCC and leaving RCC were compared, and the RSBI was significantly reduced (P < 0.05), similar to the results of Lin et al. 24 .

Muscle consumption of patients using respirators.
Breathing depends on the strength of respiratory muscles. The respiratory muscles include the diaphragm, internal intercostal muscles, external intercostal muscles, scalene muscles, and sternocleidomastoid muscles. In chronic obstructive pulmonary disease studies, the diaphragm was confirmed that the strength of respiratory muscles (PImax and PEmax) is closely related to body weight and receptor tissue (lean body mass) 25 .
In this study, the average muscle mass distribution in the right arm (RA) was 2.5 ± 1.3 kg; left arm (LA), 2.3 ± 0.8 kg; trunk (TR), 19.5 ± 5.0 kg; right leg (RL), 5.4 ± 1.7 kg; and left leg (LL), 5.3 ± 1.8 kg, and when leaving the RCC, RA was 2.3 ± 1.3 kg; LA, 2.3 ± 1.3 kg; TR, 19.0 ± 6.5 kg; RL, 5.1 ± 1.3 kg; and LL, 5.0 ± 1.7 kg. The results showed that the average muscle mass distribution of RL and LL decreased during the training process of the successfully detached from the respirator group, but this was not significant, while those of RA, LA, and TR decreased significantly (P < 0.05) ( Table 4).
The results showed that the weight loss and muscle loss of the successfully detached from the respirator group were mainly concentrated in the TR and upper limb muscles. In contrast, the unsuccessful weaning group had no weight or muscle loss. It is speculated that it may be the same as the unsuccessful weaning group during breathing training. It is related to the interruption of breathing training and rest more often.
Malnutrition and weight change in severely ill patients. Wu et al. 26 found that failure of respiratory detachment was related to a lower serum albumin level (albumin level < 2.6 g/dL, odds ratio = 5.1; 95% confidence interval = 1.04-24.66).
In the successful weaning group, RSBI, which was a respirator detachment index, was 89.8 ± 42.7 bpm/L and decreased to 71.1 ± 40.8 bpm/L (P < 0.05), and the PImax value did not change between entering and leaving the RCC, indicating that the tidal volume increased, the respiratory rate decreased, and the inspiratory force was maintained; therefore, the participants had less laborious breathing (Table 2). In addition, during training without breathing apparatus, weight loss (P < 0.05) and muscle loss (P < 0.05) were both significant, and the area of muscle loss was mainly concentrated in the breathing muscles, including TR and upper limbs (RA, LA); therefore, during the off respirator training period, the patient still needed enough calories and protein. Finally, when the participants in this group left the RCC, the serum albumin concentration of patients increased significantly compared to that before entering the RCC (pre: 2.2 ± 0.3 g/dL, back: 2.5 ± 0.4 g/dL; P < 0.05), and the total water content was significantly reduced compared to that before (before: 28.3 ± 7.0 kg, after: 27.0 ± 6.4 kg; p < 0.05), indicating that the participants' metabolism gradually recovered. This result is similar to the systematic and integrated analysis conducted by Stieff et al. 27 .
In the unsuccessful weaning group, there were no significant differences in body weight, respirator detachment parameters, and muscle mass distribution between entering and leaving RCC. However, in this group, the number of patients who were supplemented with serum albumin by intravenous injection was higher than those who did not require supplementation (Table 1). This result may be related to the disease and edema treatment. Therefore, the number of days of respirator use and RCC hospitalization was longer.  28 . In addition, the unsuccessful weaning group had longer RCC days, lower PImax, and APACHE II scores for disease severity than did the unsuccessful weaning group. In this study, there was no significant difference in the serum albumin concentration between the groups. However, the serum albumin concentration increased significantly in the successful weaning group (P < 0.05) ( Table 5). This result is similar to that reported by Wu et al. 28 . The serum albumin concentration can be used to indicate a detachment from a respirator.

Limitations, and future research directions
These data were measured by different technicians, and the measurement consistency between the technicians is unclear. Therefore, future studies can use similar research team methods to strengthen the research. In this study, anthropometrics and BIA were used. This method is based on the resistance of human adipose tissue, which may be interfered by fluid and muscle even though it is really small. The difference in resistance was used to estimate the body fat. The ratio applies to those aged 20-98 years, and its accuracy is similar to those of DEXA and other methods 19,20 .
Though the albumin is the most common value to reflect the nutritional status in clinical, it could be low when systemic inflammation happened. Inflammation and malnutrition both reduce albumin concentration by decreasing its rate of synthesis so it usually should not be used as a nutritional marker after supplementation in hospitalized patients.
During respirator disengagement, muscle consumption is concentrated in the breathing muscles (upper limbs and TR). It is recommended that more rigorous longitudinal continuity be used in the future. Interventional experimental research to continuously track changes in dietary intake, blood biochemical values, muscle mass, and muscle function of RCC patients as indicators of causality determination are warranted to improve respiratory muscle functions and effectiveness of ventilator detachment. It is recommended that future studies increase the sample size in a multi-center setup to increase the generalizability of research results.

Conclusion
This study assessed the difference between patients who were weaned off from respirators and those who remained dependent on respirators. We found that RSBI was lower, and serum albumin concentration was higher in the successful weaning group. Additionally, weight loss and changes in body muscle composition during www.nature.com/scientificreports/ training were more profound in the upper body and torso-related breathing muscles than in others. Finally, these results show that improved nutritional status aids in weaning RCC patients from respirators.

Data availability
The data that used and/or analyzed during the current study are available from the corresponding author on reasonable request.