Development and validation of a new score for predicting functional outcome of neurocritically ill patients: The INCNS score

Summary Aims To develop and validate a novel score for prediction of 3‐month functional outcome in neurocritically ill patients. Methods The development of the novel score was based on two widely used scores for general critical illnesses (Acute Physiology and Chronic Health Evaluation II, APACHE II; Simplified Acute Physiology Score II, SAPS II) and consideration of the characteristics of neurocritical illness. Data from consecutive patients admitted to neurological ICU (N‐ICU) between January 2013 and June 2016 were used for the validation. The modified Rankin Scale (mRS) was used to evaluate 3‐month functional outcomes. APACHE II scores, SAPS II scores, and our novel scores at 24 hours and 72 hours in N‐ICU were obtained. We compared the prognostic performance of our score with APACHE II and SAPS II. Results We developed a 44‐point scoring system named the INCNS score, and it includes 19 items which were categorized into five parts: inflammation (I), nutrition (N), consciousness (C), neurological function (N), and systemic function (S). We validated the INCNS score with a cohort of 941 N‐ICU patients. The 72‐hours INCNS score achieved an area under the receiver operating characteristic curve (AUC) of 0.828 (95% CI: 0.802‐0.854), and the 24‐hours INCNS score achieved an AUC of 0.788 (95% CI: 0.759‐0.817). The INCNS score exhibited significantly better discriminative and prognostic performance than APACHE II and SAPS II at both 24 hours and 72 hours in N‐ICU. Conclusion We developed an INCNS score with superior predictive power for functional outcome of neurocritically ill patients.


| INTRODUC TI ON
Neurocritical illness, defined as life-threatening neurological and neurosurgical illness, is a catastrophic event with high mortality and prolonged functional dependence. [1][2][3] An accurate and specialized prognostic score for neurocritical illness will provide clinicians a useful overview to summarize clinical findings, help stratify patients in critical care researches, and facilitate more effective communication with patients and their families about goals of care, choices of treatments, and plans for transitions.
To date, there are several prognostic scores for patients in general intensive care unit (ICU), such as the Acute Physiology and Chronic Health Evaluation II (APACHE II) 4

and Simplified Acute
Physiology Score II (SAPS II). 5 Meanwhile, some scales were also developed for specific critical illnesses, such as the Ventilator-Associated Pneumonia PIRO Score, 6 Obstetric Early Warning Score, 7 Oncological Pediatric Risk of Mortality Score (O-PRISM), 8 the Edinburgh Cardiac Surgery Score, 9 Initiation of Renal Replacement Therapy (IRRIV) Score 10 and so on. However, so far there is no prognostic score for patients with neurocritical illness who have characteristics distinct from that of patients with other critical illnesses.
And the lack of assessment of neurological deficits in those risk adjustment models biases the severity evaluation and outcome prediction in patients with neurocritical illnesses.
Glasgow coma scale (GCS) 11 and the Full Outline of UnResponsiveness (FOUR) score 12 are common methods for bedside assessment of impairment of conscious level, 13 and are widely used in neurological intensive care unit (N-ICU). Although these two scales are strongly associated with severity and outcome which are assessed by other indices, [14][15][16] the assessment of consciousness per se is unable to make comprehensive predictive statements.
Given the paucity of prognostic scores in neurocritical illness, we aimed to develop a novel score for prediction of 3-month functional outcome in neurocritically ill patients, and compare it with APACHE II and SAPS II in a cohort of neurocritically ill patients.

| Hypothesis generation
We hypothesized that a specialized score for neurocritical illness would be the combination of systemic condition evaluation and neurological function assessment. Since the variables in APACHE II and SAPS II were derived from expert consensus and large cohorts of general critical illness 4,5 and have been validated all over the world, [17][18][19][20][21] we believed that the integration and modification of these two scores would provide a reliable and reasonable basis for evaluating systemic condition accurately. Measurements concerning different aspects of neurological deficits and being routinely used in N-ICU were also considered. The process of the generation of the novel score named INCNS is depicted in  On the basis of 22 different variables in APACHE II and SAPS II, reductions and additions were made in order to form a prognostic score for neurocritical illnesses with good accuracy, availability, and ease of use. The reduction procedure followed three principles: (a) simplify congeneric items (systolic blood pressure was retained, and mean arterial pressure was removed; serum creatinine was retained, and blood urea nitrogen and urine volume were removed; co-morbidities were removed because their severities could be partly mirrored by the remaining variables); (b) suspend the variables which have not been fully proven to exert direct impacts on functional outcomes of neurocritical illnesses (hematocrit was removed; reasons for ICU admission were also removed, because some patients who don't need emergency surgery might have much poorer outcomes than those who need, such as the patients with acute intoxication or cardiac arrest for instance); (c) reduce the bias caused by common missing values: blood gas analysis (pH, PaO2) or serum HCO 3 is not necessary for each neurocritically ill patient. The addition procedure followed two principles: (a) incorporate some routine neurologic examinations in N-ICU (papillary light reflex, corneal reflex, muscle strength test, consiousness test, and water swallow test); (b) include biomarkers which are associated with functional outcomes of common neurocritical illnesses (blood glucose and serum albumin). Previous studies proved that abnormal blood glucose and serum albumin levels were independently related to the mortality and morbidity in some common neurologic diseases, such as stroke [22][23][24][25][26][27][28][29] and status epilepticus. 30,31 After the above reduction and addition procedures, 19 variables were finally determined. In order to make those variables easier to understand and remember, we grouped them into five categories: inflammation, nutrition, consciousness, neurological function and systemic condition (INCNS for short).

| Definition of the variables
White blood cell, serum albumin, random blood glucose, serum sodium, serum potassium, serum creatinine, and total bilirubin are routine labs. Temperature, respiration, heart rate, and systolic blood pressure are vital signs. Consciousness is evaluated from two aspects: (a) arousal, assessed by eye opening test (spontaneous, to verbal command, to pain, and no response); (b) awareness, assessed by behavioral tests (correct or confused behavioral responses to question or command) and tests for non-reflex movements (visual pursuit or non-contingent behaviors). The assessment of arousal status is derived from GCS which is included in APACHE II and SAPS II. The behavioral tests for awareness are routine bedside examinations in N-ICU. The examiner may ask a question about the patient's name or command the patient to move eyeballs and/or hands, if appropriate. A clear and accurate answer was considered correct, and a clearly intentional communicative response, such as head nods/shakes and thumbs up, was considered as confused.
For the patients who are unable to communicate, tests for non-reflex movements were performed. Non-reflex movements include visual pursuit, orientation to pain or non-contingent behavior (eg smiling to the presence of a family member and not to others). 32 Neurologic function is evaluated from six aspects: the intubated patients, their verbal function is scored as no verbal response. The muscle strength test is also used to assess the motor function. Either the muscle strength test or motor response to painful stimulus is performed in each patient. Patients who are unable to cooperate with muscle strength test choose the motor response to painful stimulus test. To be noted, unlike GCS score that records the best motor response from any limb, the worst motor response from any limb is recorded in our score. Swallowing function is assessed by the 30 mL water swallow test. In APACHE II the respiratory function is measured only by the respiratory rate no matter the patient is ventilated or non-ventilated. However, the respiratory function of the ventilated patients usually is much poorer than those who don't need mechanical ventilation. Therefore, we classified the respiratory function into four degrees: (a) not intubated, respiratory rate of 12 to 24; (b) not intubated, respiratory rate ≤ 11 or ≥25; (c) breathes above ventilator rate; (d) breathes at ventilator rate or apnea.

| Weight assignment
In order to make this score easy to calculate and use, the weighing system was based on a simple scale of 0 to 3 (like APACHE II) instead of a sophisticated scale of irregular numbers (like SPAS II) generated by statistic calculation. 0 denotes normal, and a higher score means a more serious condition. Considering that brainstem function tests play a pivotal role in outcome prediction, we assigned higher scores to the slow and absent responses of papillary light reflex and corneal reflex.
F I G U R E 1 Flow chart for the variable generation of the INCNS score. ALB albumin, APACHE II Acute Physiology and Chronic Health Evaluation II, BUN blood urea nitrogen, MAP mean artery pressure, N-ICU neurological intensive care unit, SAPS II Simplified Acute Physiology Score II, SBP systolic blood pressure, SCr serum creatinine, WBC white blood cell

| Population
This analysis was based on a prospective database of all the patients admitted to N-ICU in Xijing Hospital, a tertiary academic medical care institution with 3200 beds in Xi'an, China. Consecutive patients who have stayed in N-ICU for longer than 72 hours between January 2013 and June 2016 were used for the validation of the INCNS score. The ethics committee of the Xijing hospital reviewed and approved the study. All the procedures were carried out in agreement with Chinese laws and the Helsinki declaration relative to patients' rights.

| Data collection
The data concerning all the variables included in APACHE II, SAPS II, and INCNS score were reviewed. The most deranged reading during each patient's initial 24 hours and 72 hours in N-ICU were recorded and used in the validation analysis. All the neurologic examinations involved in these three scores are daily routines in N-ICU, and were performed by the neurologist who was in charge of each patient.

| Definition of outcomes
The modified Rankin Scale (mRS), a seven-point scale ranging from 0 (no symptoms) to 6 (death), was used to evaluate the functional outcome 3 months after the discharge from N-ICU, by a trained research assistant who was blinded to clinical data. A mRS score < 3 was considered favorable (independence), and a mRS score ≥ 3 was considered unfavorable (dependence or death).

| Statistical analysis
Continuous variables were expressed as mean ± SD or median (in-

| RE SULTS
The INCNS score was presented in Table 1.  Tables S1 and S2 respectively. The etiology distribution in this cohort was provided in Table S3.   Figure 3, Table S4). Figure 4 showed that the probability of an unfavorable outcome of neurocritically ill patients increased as the 72hours INCNS score rose.

| Comparison of INCNS, APACHE II and SAPS II score
Overall performances of INCNS, APACHE II and SAPS II were presented in Figure 2, Figure 3 and and CC of the INCNS score were also significantly higher than those of APACHE II and SAPS II at both 24 hours and 72 hours ( Figure 3, Table S4). Moreover, the INCNS score showed much better discriminative performance compared with GCS (24 hours: P < 0.0001; 72 hours: P < 0.0001) and FOUR (24 hours: P < 0.0001; 72 hours: P < 0.0001) at both 24 hours and 72 hours as well ( Figure S1).  sponse test was also modified. The worst motor response from any limb rather than the best one is recorded in our score, because the purpose of the INCNS score is to predict 3-month functional outcome, and the disability of any limb will definitely impair motor skills.

| D ISCUSS I ON
Arousal and awareness are essential parts of consciousness.
Arousal is the psychological and physiological state of being awoken, and awareness is the ability to perceive or to be cognizant of the selfexistence and events. In INCNS score, we used the eye opening test, behavioral tests and tests for non-reflex movements to evaluate the levels of arousal and awareness. The INCNS score also includes the assessments of brainstem reflexes and swallowing function. The pupillary light reflex and corneal reflex are routine neurologic examinations in N-ICU and convenient approaches for assessing the function of brainstem, which plays a pivotal role in maintaining many basic functions, such as consciousness, breathing, heart rate, and sleeping.
As a common result of a variety of neurological diseases (cerebral infarction, intracerebral hemorrhage, traumatic brain injury, myasthenia gravis, dementia, etc), 36 dysphagia is associated with some unfavorable outcomes, including pneumonia, reintubation, in-hospital mortality and prolonged hospital length of stay. [36][37][38][39] Moreover, the difficulty in swallowing will also affect the quality of life in long term. Therefore, the water swallow test was adopted to assess the swallowing function. All the neurologic examinations used in INCNS score are common and routine tests, and have been proven to possess excellent interrater reliability. [40][41][42] APACHE II and SAPS II were established based on the worst values of the measurements during the first 24 hours in general ICU. 4,5 However, some studies suggested that a severity score (APACHE II or the mortality probability models) that performed at 72 hours in ICU worked much better than the one performed on admission, 24 hours or 48 hours. 43,44

| CON CLUS IONS
We established a novel risk prediction score, named INCNS, to predict the 3-month functional outcome of neurocritically ill patients.

ACK N OWLED G EM ENTS
The study was supported by the Natural Science Foundation of China (81571262) and the Shaanxi Province Key Research and Development Project (2017ZDCXL-SF-02-02). The authors sincerely thank all persons who participated in the study.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interest.