Relationship between cerebral hemodynamics, tissue oxygen saturation, and delirium in patients with septic shock: a pilot observational trial

Background Patients with septic shock are prone to have impaired cerebral autoregulation and to have an imbalance in cerebral oxygen metabolism. Transcranial doppler (TCD) and tissue oxygen saturation monitoring were performed to observe the changes in cerebral hemodynamic indices of the middle cerebral artery, and in cerebral and peripheral tissue oxygen saturation (StO 2 ) to identify risk factors for sepsis-associated delirium (SAD). Methods Patients with septic shock that were admitted to the Department of Critical Care Medicine of Hospital of Central South University from May 2018 to March 2019 were prospectively enrolled, which were divided into an SAD group and a non-SAD group according to the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Both groups were compared with respect to patient characteristics, blood gas analysis indexes, organ function indicators, cerebral hemodynamic index, cerebrovascular automatic regulation function (transient hyperemia response rate, THRR index), the changes in regional cerebral oxygen saturation, and peripheral tissue oxygen saturation.


Background
Sepsis-associated delirium (SAD) is considered a diffuse cerebral dysfunction caused by a systemic in ammatory response to an infection without evidence of a central nervous system involvement (i.e., infection). SAD can develop in a short time and uctuate transiently with time [1][2]. Studies have found that neuroin ammation, abnormal cerebral perfusion, neurotransmitter imbalances and neuronal degeneration may be involved in the pathogenesis of SAD [3][4][5][6]. Other studies suggest that changes in cerebral blood ow caused by hemodynamic instability, decreased brain oxygen uptake, blood-brain barrier disruption and cerebral edema are important predisposing factors for SAD [7][8]. Transcranial Doppler (TCD) ultrasound can visually detect the changes of cerebral perfusion and cerebral autoregulation in patients with sepsis. P ster et al. [9] found a signi cant correlation between cerebral vascular autoregulation disorders and SAD. Some studies have found that the changes of cerebral hemodynamics detected by TCD ultrasound are closely related to the clinical symptoms of SAD [10].
Hypotension and hypoxia not only increase neuronal apoptosis but are also directly associated with poor prognosis [11]. At present, for both central venous oxygen saturation(ScvO 2 )and Mixed venous oxygen saturation(SvO 2 ), the monitoring is non-continuous, requires invasive procedures, and does not allow speci c monitoring of local brain tissue, which makes it impossible to quickly and effectively identify patients with sepsis who are at risk of brain or brain-tissue hypoxia [12]. Regional cerebral oxygen saturation (rSO 2 ) and tissue oxygen saturation (StO 2 ) monitoring which are derived from near infrared spectroscopy (NIRS) can provide non-invasive assessment of cerebral oxygen metabolism and local tissue oxygen metabolism, providing real-time and continuous information of the balance of oxygen supply and demand. In addition, rSO 2 is a sensitive indicator of global cerebral hypoperfusion [13].
Studies have revealed a good correlation between tissue oxygen saturation monitoring and clinical evaluation of sepsis or septic shock [14][15].
Therefore, our study uses TCD and tissue oxygen saturation monitoring to observe the changes in cerebral hemodynamic indices of the middle cerebral artery, and in cerebral and peripheral tissue oxygen saturation (StO 2 ) to identify risk factors for sepsis-associated delirium (SAD).

Patients
Fifty-one patients with septic shock who were admitted to the Department of Intensive Care Unit, Xiangya Hospital of Central South University from May 2018 to March 2019 were enrolled in our study. Our study was a pilot observational trial with inclusion criteria were in accordance with the de nition of sepsis 3.0. All included patients were treated according to the 2016 International Guidelines for the Treatment of Sepsis and Septic Shock [16] (i.e., Mean arterial pressure (MAP) reached 65 mmHg and lactic acid normalization was the target of initial resuscitation). Patients with diagnostic criteria for septic shock [17] were included in the study. Exclusion criteria: (1) age < 18 years ; (2) previous history of mental disorders or craniotomy; (3) neurological diseases (clear intracranial lesions such as cerebral hemorrhage, subarachnoid hemorrhage, craniocerebral trauma, stroke, intracranial infection, etc.); (4) liver failure with hepatic encephalopathy suspected; (5) pregnancy; (6) abnormal ndings upon cervical vascular examination, by head MRI/CT and TCD ultrasound (such as carotid plaque with hemodynamically signi cant stenosis (eg > 50%)., thrombosis, etc.); (7) inability to detect blood ow signals in the temporal window by TCD. The primary outcome was delirium from admission to the ICU to Day 7 or discharge from the ICU.The secondary outcome was the 28-day mortality rate.

Ethics approval and consent to participate
This study was conducted in line with the standards of medical ethics. It was approved by the Central South University Xiangya Hospital Ethics Committee (Ethics No.:2018101082), and informed consent was obtained from the patient's immediate families.
Evaluation method of delirium The diagnosis of delirium was based on the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU), which was performed twice a day by trained researchers at the ICU (10:00-11:00 am; 16:00-17:00 for at rst day of ICU admission up to 7 days. Patient assigned to the "SAD group" on the basis of a twice positive CAM-ICU screen performed by two researchers. All patients with septic shock were classi ed into a SAD group and non-SAD group according to the presence or absence of delirium, respectively.

Data collection
General data, Acute physiological and chronic health status assessment scores (APACHE II) score, sequential [sepsis-related] organ failure assessment (SOFA) score, administration of sedation and analgesia drugs, continuous renal replacement therapy (CRRT) mechanical ventilation time (days), ICU time (days), and 28-day mortality (%) of septic shock patients were determined.

Circulating hemodynamic management indicators
Arterial and central venous blood gas indicators, lactate clearance, Central venous pressure (CVP), Norepinephrine dosage, total resuscitation uid, and urine output. Patients with septic shock included in the study completed critical echocardiography within 1 hour of admission, which measured cardiac output (CO), left ventricular ejection fraction (LVEF%), inferior vena cava diameter (IVCD), and Inferior Vena cava collapse index (IVC-CI).

Organ function and biochemical markers
Blood samples were monitored immediately after admission to the ICU, including organ function was assessed using routine blood indicators, liver and kidney function indicators, and routine coagulation indicators. Sepsis-associated biomarker indicators were procalcitonin (PCT); Neuron Speci c Enolase (NSE), Central Nervous System Speci c Protein (S100β). TCD monitoring index TCD ultrasound (Shenzhen Delikai, EMS-9A dual channel, 1.6 MHz TCD probe) was used to obtain the bilateral middle cerebral arteries (MCAs) ow signal through the temporal window after 6 hours of initial resuscitation in patients with septic shock. Recording the diastole velocity of middle cerebral arteries (Vd MCA ), mean blood ow velocity (the mean velocity of middle cerebral arteries;Vm MCA ), systolic velocity of middle cerebral arteries (Vs MCA ),pulsatility index (PI;PI=(Vs MCA -Vd MCA )/Vm MCA ), and calculation of cerebral blood ow index (CBFi, CBFi = 10 × MAP/1.47 PI), record whether the S 1 and S 2 peaks are fused during systole, and complete the dynamic assessment of cerebrovascular autoregulation. Dynamic cerebrovascular autoregulation was assessed by the transient hyperemia response rate (THRR) method. That is, the blood ow velocity of the middle cerebral artery was stably decreased to 30-50% of the baseline value by con rmed carotid artery compression for 3-9 seconds, and then the ratio of the blood ow velocity to the baseline blood ow velocity was measured. A THRR index > 1.09 is considered evidence for a dynamic cerebrovascular autoregulation function, conversely, at a THRR index ≤ 1.09 cerebrovascular autoregulation is considered to be impaired [18].
Tissue oxygen saturation was determined using the non-invasive tissue oxygen saturation monitor (CASMED, FORE-SIGHT) to continuously collect forehead cerebral oxygen saturation (rSO 2 ) (Large probe, detection depth 2.5 cm below the skull) and the thenar eminence tissue oxygen saturation (StO 2 ) (small probe, detection depth 0.5-2 cm). rSO2 and StO2 values were continuously recorded for at least 1 hour after 6 hours of initial resuscitation in patients with septic shock, and these data were uniformly processed in the later period. The rSO2 and StO2 data were analyzed at multiple thresholds ( 65%, < 60%, < 55%, and < 50%) to determine 1 suitable for comparison [19].
Data analysis SPSS version 24.0 (SPSS Inc, Armonk, New York) was used for data analysis. The data were tested for normality. The data of the continuous variable that conformed to or approximated the normal distribution were expressed as mean ± standard deviation (χ ± s). The comparison between two samples was performed by independent student t test. Data that did not conform to the normal distribution were expressed as median [interquartile range; IQR], and the comparison between the two samples was performed using the Wilcoxon rank-sum test. The chi-square (X 2 ) test was used to compare categorical data. When the theoretical frequency was < 5, the continuous correction method was adopted. When the theoretical frequency was < 1, the exact probability method was adopted. Multivariate logistic regression analysis was used to detect independent predictors of delirium, the predictor variables were selected from the risk factors displaying p < 0.05 in tables. The Pearson analysis method was used to analyze the correlation of the above-mentioned normal distribution variables. P < 0.05 was considered statistically signi cant.

Results
Of a total of 121 patients with septic shock that were screened in this study, 66 patients met the exclusion criteria and 4 patients did not complete delirium evaluation. Therefore, 51 patients were enrolled in the study after CAM-ICU evaluation was successfully completed. SAD incidence was 39%. (Fig. 1).

Circulating hemodynamics indicators
Compared with the non-SAD group, the SAD group had signi cantly higher blood lactate (Lac) (t6h) (5.2

Organ function and biochemical markers
The white blood cell count (WBC) was signi cantly higher in the SAD group than in the non-SAD group (

Tissue oxygen saturation monitoring
The mean rSO 2 value of the SAD group was lower than that of the non-SAD group (55 ± 7 vs 60 ± 6, p = 0.01). In the overall study cohort, 16 patients had an average rSO 2 value of < 55%, and this was signi cantly more predominant in the SAD group than in the non-SAD group (50% vs 19%, p = 0.021). In addition, 15 patients had a mean StO 2 < 60%, which was also signi cantly more predominant in the SAD group than in the non-SAD group (45% vs 19%, p = 0.049) ( Table 3).

Discussion
Impaired cerebral hemodynamics and imbalance of cerebral oxygen metabolism play an important role in the development of SAD. Our study con rmed a high incidence of SAD among patients with sepsis, which was associated with poor prognosis. Cerebrovascular autoregulation dysfunction (THRR index < 1.09) and mean cerebral oxygen saturation < 55% were found to be independent risk factors for SAD.
First, our study showed that the incidence of SAD in patients with septic shock was 39% (20/51), and that the SAD group required longer mechanical ventilation and ICU stay, and had a signi cantly higher 28-day mortality rate, which highlighted the need for identifying risk factors allowing early identi cation of SAD.
In the ICU, early identi cation of reversible risk factors is very important for improving the prognosis of patients with sepsis or septic shock [20]. Tse et al. [21] proposed that age as well as certain pre-existing diseases and conditions are predictors of delirium after cardiac surgery. There are no recommended drugs or drug regimens to prevent delirium, so the focus should be on non-pharmaceutical interventions, including active communication, early detection of patients' psychological problems, family companionship, early activities, noise reduction, and good sleep [22].
Second, our study showed that cerebral vascular autoregulation dysfunction was an independent risk factor for delirium in patients with septic shock. This suggests that there is a decrease in cerebral perfusion and a decrease in cerebral vascular compliance in patients with SAD 6 hours after initial resuscitation. These changes may further affect cerebrovascular autoregulation. Cerebral hemodynamics and cerebral oxygen metabolism disorders play a crucial role in the development of SAD, which also lays the foundation for clinical hemodynamic management strategies targeting cerebral perfusion. Central nervous system dysfunction caused by sepsis is closely related to cerebral hypoperfusion caused by decreased cerebral blood ow. TCD ultrasound can monitor the systolic, diastolic, and mean blood ow velocity of anterior, posterior, and middle cerebral arteries to evaluate cerebral perfusion [23]. TCD also provides an indirect assessment of the cerebral circulation including cerebral vascular autoregulation. When the cerebral vascular autoregulation is impaired, the changes of cerebral ischemia or cerebral congestion that may occur with the changes of perfusion pressure may cause nerve damage, which may adversely affect the prognosis. As early as 1997, Smielewski et al. [24] found that the disappearance of the transient cerebral congestion response rate (THRR) was associated with poor prognosis in patients with severe craniocerebral injury. Although TCD and THRR index evaluation cannot completely replace the results of brain imaging, they can provide early continuous monitoring of cerebrovascular autoregulation in patients with sepsis and septic shock [25]. The timely detection of the dysfunction of cerebrovascular autoregulation, will improve timely implementation of intervention measures.
Third, determining an imbalance between oxygen supply and demand in the optimization of cerebral perfusion requires real-time dynamic monitoring of oxygen saturation of brain. Our study found a lower mean rSO 2 value in the SAD group than in the non-SAD group, and multivariate regression showed that a mean rSO 2 < 55% was an independent risk factor for delirium in patients with septic shock. It is suggested that the overall trend of cerebral oxygen saturation in SAD patients persists at a low level. The mismatch between cerebral oxygen supply and oxygen consumption is crucial for the development of SAD, which also requires a continuous monitoring of cerebral oxygen saturation in patients with septic shock. It should be used as a routine monitoring indicator followed by blood pressure, heart rate, respiration, and pulse oxygen saturation. Studies have reported that intraoperative regional rSO 2 < 40% is an independent predictor of cognitive impairment after cardiac surgery [26]. De Tournay-Jette et al. [27] also reported that patients with rSO 2 < 50% during surgery experienced more post-operative cognitive dysfunction after 4 to 7 days of surgery (p = 0.04), and that a greater than 30% reduction in baseline rSO 2 was associated with cognitive impairment 1-month post-surgery (p = 0.03). Monitoring of oxygen saturation provides important information about oxygen in brain tissues at risk of various diseases. [28].
Fourth, the mean value of StO 2 uctuated between 60-74% after initial resuscitation in patients with septic shock. In optimizing hemodynamics in critically ill patients, although global parameters are normalized, microcirculation and regional perfusion may change. The persistence of these changes is associated with poor prognosis. StO 2 can serve as an early warning signal for the initiation of low perfusion and tissue hypoxia [29].
There are certain limitations to this study. First, the effectiveness of TCD ultrasound is in uenced by the operator's technique. Second, we only evaluated the changes of cerebral hemodynamics, and cerebral and peripheral tissue oxygen saturation 6 hours following the initial resuscitation and without combined neuroimaging or neurophysiological results. In addition, in view of the small sample size and the observational nature of our study, large-scale randomized controlled clinical trials may be needed for further veri cation of our results.

Conclusions
This group of septic patients had a high incidence of SAD and this was associated with poor prognosis. Cerebrovascular dysregulation (THRR < 1.09), and mean cerebral oxygen saturation < 55% are independent risk factors for SAD. The high-quality and adequately powered RCTs are warranted in the future.

Declarations
Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.