The sepsis-associated delirium (SAD) is regarded as a diffuse cerebral dysfunction, caused by inflammatory responses of the body to infections taking place with no discernible cause of central nervous system, i.e., infection. SAD may have a rapid onset and levels may fluctuate over time (1, 2). Research has demonstrated that pathogenesis of SAD can involve neuronal degeneration, neurotransmitter imbalance, abnormal cerebral perfusion, and neuroinflammation (3–6). Some researchers have proposed that there is a higher likelihood of SAD in patients experiencing cerebral edema, blood-brain barrier disruption, lower brain oxygen uptake, and variations in cerebral blood flow as a result of hemodynamic instabilities (7, 8). For sepsis patients, variations in cerebral autoregulation and perfusion can be visually detected by using transcranial Doppler (TCD) ultrasound. Significant links between SAD and cerebral vascular autoregulation disorders were revealed by Pfister et al. (9). Some study has found a close correlation between clinical manifestations of SAD and variations in cerebral hemodynamics found by using TCD ultrasound. Pierrakos et al. (10) found that pulsatility index (PI) on the first day could predict the positive Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) test in sepsis patients (p < 0.01) and only on the first day, the mean blood velocity in the middle cerebral artery (MCA) and cerebral blood flow index (CBFi) was found to be lower in those patients with a high initial PI.

Hypoxemia and hypotension lead to an increase in neuronal apoptosis and, further, have direct associations with poor outcomes (11). Current methods for monitoring mixed venous oxygen saturation (SvO₂) and central venous oxygen saturation (ScvO₂) are non-continuous, demand invasive procedures, and do not permit pinpointed local brain tissue monitoring, meaning that rapid and effective identification of sepsis patients with higher risks of suffering brain/brain-tissue hypoxemia is not possible (12). Monitoring tissue oxygen saturation (StO₂) and regional cerebral oxygen saturation (rSO₂) by using near-infrared spectroscopy (NIRS) offers a noninvasive means of assessing cerebral and local tissue oxygen metabolism, offering continuous real-time data regarding the balance between demand and supply for oxygen. Additionally, rSO₂ is a sensitive marker for global cerebral hypoperfusion (13). This study has demonstrated that monitoring of StO₂ is a useful means of clinically evaluating sepsis/septic shock (14, 15).

In light of the above, this research employs TCD and StO₂ monitoring for observation of the variations in the cerebral hemodynamic indices of the MCA and also variations in cerebral/peripheral StO₂ for identification of elements that increase the risk of patients developing SAD.

A total of 121 septic shock patients were evaluated for this study; a total of 66 of them fulfilled one or more of the exclusion criteria and four patients did not undergo a full delirium evaluation. Finally having successfully completed the CAM-ICU evaluation, a cohort of 51 patients was selected for the research. About 39% experienced SAD (Figure 1).

Imbalances in cerebral oxygen metabolism and impairment of cerebral hemodynamics are key factors in whether or not patients develop SAD. This study confirms that there are high rates of SAD in septic shock patients and it has associations with poor outcomes. It has been shown that independent risk factors for the condition are mean cerebral oxygen saturation below 55% and cerebral vascular autoregulation dysfunction (THRR index < 1.09).

The first point to note in this study is that 39% of septic shock patients were suffering from SAD (20/51); this group had the higher APACHE II and the SOFA scores, needed more time on mechanical ventilators and longer stays in ICU, and their 28-day survival rate was significantly lower. This demonstrated that SAD has a close correlation with severe illness and poor outcomes. So, it is important to identify patients who were at risk for developing delirium. Mori et al. (20) showed a high incidence of ICU delirium associated with older age, use of sedatives and analgesics, emphasizing the need for relevant nursing care to prevent and identify early patients presenting these characteristics. Tse et al. (21) have suggested that delirium following cardiac surgery is influenced by age and several underlying diseases/conditions. Drugs and drug regimens for the prevention of delirium have not currently existed, so clinicians should concentrate on the non-medication interventions; these include keeping lines of communication open, identifying any psychological difficulties patients have early, keeping patients in touch with their family promoting healthy sleep, keeping noise to a minimum, and attempting to get patients active early (22).

Second, it was demonstrated that with septic shock patients, cerebral vascular autoregulation dysfunction is an independent risk factor. This would suggest that 6 h following initial resuscitation, patients experiencing SAD have a fall in cerebral vascular compliance and cerebral perfusion. These fluctuations could have an additional impact on cerebral vascular autoregulation. Cerebral oxygen metabolism and cerebral hemodynamic disorders have a key part in developing SAD, which should inform clinical practice in managing hemodynamics with a focus on cerebral perfusion. There is a close correlation between the central nervous system dysfunction seen in sepsis and cerebral hypoperfusion as a result of a fall in cerebral blood flow. Cerebral perfusion can be evaluated through monitoring of systolic, diastolic, and mean blood flow velocity in the anterior, middle, and posterior cerebral arteries by using TCD ultrasound (23). TCD also offers an indirect means of assessing cerebral circulation, which includes cerebral vascular autoregulation. With impairment in cerebral vascular autoregulation, fluctuations in perfusion pressure can cause cerebral congestion or ischemia resulting in nerve damage, which can have a negative impact on outcomes. In 1997, Smielewski et al. (24) discovered a correlation between a vanished transient cerebral congestion response rate (THRR) and poor outcomes for patients who had suffered serious craniocerebral injuries. While the value of brain imaging cannot be completely substituted for TCD and THRR index evaluation, they provide a means of continually monitoring cerebrovascular autoregulation in the early stages of treatment for sepsis/septic shock patients (25). Early identification of cerebrovascular autoregulation dysfunction will allow clinical interventions to take place earlier.

Third, the oxygen saturation of the brain has to be dynamically monitored in real time if cerebral perfusion is to be optimized by determining any oxygen supply/demand incompatibilities. This study demonstrated that the group with SAD had lower mean rSO₂ values than those who did not; the multivariate regression illustrated that for septic shock patients, a mean rSO₂ < 55% increases the likelihood of delirium. It appears that generally, patients with SAD have low levels of cerebral oxygen saturation. Discrepancies between oxygen consumption and cerebral oxygen supply are key to patients developing SAD and so septic shock patients must be continually monitored for cerebral oxygen saturation levels. As with heart rate, respiration, blood pressure, and pulse oxygen saturation, cerebral oxygen saturation level should become a standard monitoring indicator. The study has shown that intraoperative regional rSO₂ levels below 40% represent a significant independent risk factor for cognitive impairment following cardiac surgery (26). According to De Tournay-Jette et al. (27), it has been reported that subjects with a rSO₂ below 50% in the course of surgery had greater levels of cognitive dysfunction postoperatively 4 to 7 days after surgery (p = 0.04) and that patients who have experienced a reduction in relation to their baseline rSO₂ of more than 30% were more likely to display cognitive impairment 1 month after their surgery (p = 0.03). When oxygen saturation is monitored, it offers essential data regarding brain tissue levels of oxygen that can be impacted by several diseases (28).

Finally, mean StO₂ values varied from 60 to 74% following the initial resuscitation of septic shock patients. While there are normalized global parameters for hemodynamics, optimization of them may result in changes in regional perfusion and microcirculation. If these changes persist, a poor outcome is more likely. StO₂ may function as an early alert to the fact that tissue hypoxia/low perfusion is beginning (29).

This study has some limitations. First, the ability of the technician can influence how effective TCD ultrasound can be. Second, evaluation was only undertaken of variations in cerebral hemodynamics and oxygen saturation in cerebral and peripheral tissue 6 h after initial resuscitation; we did not combine this with neurophysiological findings or neuroimaging. Third, patients with unattainable TCD flow spectrum or with a carotid plaque were excluded, which will affect its application to the entire septic shock patient population. As this study was observational in design and only involved a small patient cohort, randomized controlled trials (RCTs) on a larger scale may be necessary to verify our findings.

Patients with SAD have a close correlation with poor outcomes. Independent risk factors for SAD were mean cerebral oxygen saturation below 55% and cerebrovascular dysregulation (THRR < 1.09). This would justify the provision of RCT with adequate power for patient treatment in the future.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This prospective observation study was undertaken at an academic hospital in an urban area of China. All patients involved gave written informed consent for their participation in this study. The Ethics Committee of Xiangya Hospital of Central South University approved all elements of this research (Ethics no: 2018101082). The patients/participants provided their written informed consent to participate in this study.

QF undertook the statistical analysis, researched the scientific literature, and drafted the manuscript. MA, LH, and QP assisted in data collection. YA made contributions to the initial concept, design, and data interpretation. LZ also made contributions to the initial concept, design, data interpretation, editing, revision of the manuscript, and supervised this study. The manuscript has been reviewed and approved by all the authors.

This study benefitted from support in the form of grants from the Chinese National Natural Science Foundation, China (81873956).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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