Severe brain injury ICU outcomes are associated with Cranial-Arterial Pressure Index and noninvasive Bispectral Index and transcranial oxygen saturation: a prospective, preliminary study

The primary clinical objective after severe brain trauma is to prevent secondary injury, a common sequel to the primary, mechanical impact. The concept is to prevent cerebral hypoxia by maintaining sufficient oxygen delivery to meet the oxidative metabolic needs of the intracranial neural tissues. This implies that cerebral blood flow, arterial oxygen saturation, and hemoglobin concentration in a specific patient need to be adequate.

Intracranial pressure (ICP) and cerebral perfusion pressure (CPP) (mean arterial pressure (MAP) - ICP) monitoring is recommended for severe brain injury. There are several limitations of ICP and CPP monitoring: the ICP device is invasive and insertion requires rigorous training [1, 2]; distinct ICP and CPP target recommendations are uncertain [3, 4]; CPP is not equivalent to cerebral blood flow [5]; and, additionally, arterial oxygen content (arterial oxygen saturation (SaO₂) and hemoglobin) and oxidative cerebral tissue needs, relative to oxygen delivery, are not intrinsic components of ICP and CPP.

Near-infrared oximetry provides a noninvasive method for measuring transcranial oxygen saturation (StcO₂). StcO₂ estimates regional cerebral capillary/venous oxygen saturation [6‐8] StcO₂ monitoring provides an opportunity to determine whether cerebral cortical oxygen delivery is adequate to meet cellular oxidative needs. Dunham and colleagues have shown that cerebral oximetry values correlate with outcomes and CPP following severe brain injury [9]. These findings have been corroborated by others [10].

A repertoire of electrical activity continuously emanates from the superficial cerebral cortex and can be displayed on an electroencephalogram (EEG). EEG tracings have been shown to be variably altered by sedatives, hypoxia, hypercarbia, ischemia, and intracranial hypertension [11]. The noninvasive, Bispectral Index (BIS) monitor creates a computer-processed summary of EEG brain wave activity [12]. The algorithm generates an ordinal number that rates level of hypnosis during anesthesia. Although BIS values have been shown to correlate with some intensive care unit (ICU) conditions, documented experience with severe brain injury is limited.

CPP monitoring is an attempt to estimate global cerebral blood flow. StcO₂ monitoring assesses frontal cerebral cortical oxygen extraction (the relationship between oxygen delivery and consumption). BIS values are influenced by frontal cortical electrical activity. The study purpose is to determine the relationships between StcO₂ and BIS values in severe brain injury and ICU outcomes (survival, discharge Glasgow Coma Scale (GCS) score, ICP, CPP, and interventions to lower ICP).

The study includes 18 consecutive patients and was conducted from July 2005 until May 2006. There are 1,883 concurrent, hourly observations of ICP, CPP, BIS and StcO₂ values. Injury characteristics are displayed in Table 1. The data are normally distributed (MAP - W = 0.99; ICP - W = 0.89; CPP - W = 0.98; BIS - W = 0.99; StcO₂ - W = 0.99; p < 0.0001 for all variables). Surviving and good neurological outcome patients have increased CPP, StcO₂, and BIS and decreased ICP and CAP Index (Table 2). ICP, CPP, BIS and StcO₂ rates are: ICP ≤20 = 84.9% (1,598); CPP ≥60 = 93.9% (1,768); BIS ≥60 = 30.9% (582); and StcO₂ ≥70 = 50.4% (949). Survival is independently associated with ICP ≤20, BIS ≥60, and StcO₂ ≥70 (p < 0.0001). Good neurological outcome is independently associated with ICP ≤20, BIS ≥60, and StcO₂ ≥70 (p < 0.0001). Survival is independently associated with CPP ≥60, BIS ≥60, and StcO₂ ≥70 (p < 0.0001). Good neurological outcome is independently associated with CPP ≥60, BIS ≥60, and StcO₂ ≥ 70 (p < 0.0001). Interactive variables are either not statistically significant or have no impact on model predictability.

StcO₂ and BIS have an inverse association with ICP and CAP Index, and a direct association with CPP (Table 3). StcO₂ has a direct association with BIS (Table 4). Combined BIS and StcO₂ rates are: BIS ≥60 or StcO₂ ≥70 = 61.2% (1,152); and BIS <60 and StcO₂ <70 = 38.8% (731). BIS ≥60 or StcO₂ ≥70 is associated with survival, good neurological outcome, CPP ≥60, ICP ≤20, CAP Index ≤0.30, and less interventions to lower ICP (Table 5). The majority of observations for surviving and good neurological outcome patients have BIS ≥60 or StcO₂ ≥70. The majority of observations for dying and poor neurological outcome patients have BIS <60 and StcO₂ <70. With BIS ≥60 or StcO₂ ≥70, the rate for CPP ≥60 is 97.2% (95% confidence interval (CI) 96.1 to 98.0), the rate for ICP ≤20 is 90.8% (95% CI 89.0 to 92.3%), and the rate for ICP ≤25 is 97.1% (95% CI 96.0 to 98.0%).

An increasing CAP Index indicates a modest reduction in MAP and substantial increase in ICP (Table 6). As the CAP Index increases, the magnitude of change in this variable is much greater in comparison to the changes in MAP, ICP, and CPP. The CAP Index is increased with death, poor neurological outcome, and need for interventions to lower ICP (Table 7). The CAP Index has the following correlation coefficients: ICP - r = 0.70, p < 0.0001; MAP - r = -0.18, p < 0.0001; and CPP - r = -0.55, p < 0.0001. Survival is independently associated with CAP Index and CPP (p = 0.0001). Good neurological outcome is independently associated with CAP Index (p = 0.0001), but not CPP (p = 0.29). The need for interventions to lower ICP (mannitol and/or CSF aspiration) is independently associated with CAP Index and ICP (p = 0.0001). The need for interventions to lower ICP (mannitol and/or CSF aspiration) is independently associated with CAP Index (p = 0.0001), but not CPP (p = 0.08). When the CAP Index is >0.25 (n = 365; MAP - 91.0 ± 12.0; ICP - 27.1 ± 9.1; CPP - 64.0 ± 14.6), there is no relationship between MAP and ICP (r = 0.07; p = 0.16)

This is a prospective study evaluating 18 consecutive patients with severe brain injury. It includes 1,883 hourly concurrent observations of ICP, CPP, BIS and StcO₂. The study findings indicate that BIS and StcO₂ are clinically relevant variables, because they are associated with ICU outcomes (survival, hospital discharge GCS, ICP, CPP, and interventions to lower ICP). Surviving patients and patients with good neurological outcome have higher BIS and StcO₂ values. BIS and StcO₂ are inversely related to ICP and CAP Index and directly associated with CPP. BIS and StcO₂ have a positive relationship. The data suggest that BIS, StcO₂, ICP, and CPP are related, but distinct indices of outcome.

ICP and CPP monitoring have substantial limitations. There are insufficient data to support a treatment standard for ICP treatment threshold, a principle that reflects a high degree of clinical certainty [3]. ICP treatment should be "initiated at an upper threshold of 20 to 25 mmHg", a principle that reflects a moderate degree of clinical certainty [3]. The moderate degree of clinical certainty, the nebulous recommendation to initiate treatment, and the ICP range indicate that a precise ICP endpoint has not been realized. There are insufficient data to support a treatment standard for a targeted CPP, a principle that reflects a high degree of clinical certainty [4]. CPP should be maintained at a minimum of 60 mmHg, a principle that reflects a moderate degree of clinical certainty. Further, ICP devices are invasive and insertion requires expertise [1, 2]. Further indication that ICP and CPP targets are unclear is the controversy between CPP versus ICP management [13‐15] Additionally, CPP does not equate to cerebral blood flow [5]. Finally, arterial oxygen content (SaO₂ and hemoglobin) and oxidative cerebral tissue needs, relative to oxygen delivery, are not components of ICP and CPP. These ICP and CPP constraints suggest that additional monitoring techniques are needed.

The multiple associations of BIS and StcO₂ with survival, neurological outcome, ICP, and CPP suggest that BIS and StcO₂ are clinically discriminate parameters. Surviving patients have decreased ICP, increased CPP, decreased CAP Index, increased StcO₂, and increased BIS. Good neurological outcome patients also have decreased ICP, increased CPP, decreased CAP Index, increased StcO₂, and increased BIS. Variation in StcO₂ and BIS are associated with changes in ICP and CPP. Such statistical associations support the validity of StcO₂ and BIS and their potential clinical utility.

The independent association of BIS, StcO₂, and ICP with outcomes indicates that BIS, StcO₂, and ICP data are complementary. BIS, StcO₂, ICP, and CPP are related, but distinct indices of outcome with severe brain injury. Survival is independently associated with BIS, StcO₂, ICP, and CPP. Good neurological outcome is also independently associated with BIS, StcO₂, ICP, and CPP. Other studies indicate that supplemental monitoring in severe brain injury is associated with clinical benefits. Cruz [16] showed that managing cerebral extraction of oxygen in conjunction with CPP is associated with better neurological outcomes than when CPP treatment alone is used. Other patients with severe brain injury and receiving multi-modal monitoring have improved survival when compared to ICP and CPP monitoring [17]. The study and literature findings are in support of severe brain injury multi-modal monitoring.

The study findings indicate that, when ICP increases or CPP decreases, there is cerebral hypoxia and altered brain wave patterns. With increased ICP or decreased CPP, StcO₂ is reduced. As well, increased ICP or decreased CPP are associated with a reduction in BIS. Increased BIS is associated with increased StcO₂.

BIS ≥ 60 or StcO₂ ≥ 70 suggest that patients with severe brain injury are stable. A BIS ≥60 or StcO₂ ≥70 are associated with survival, good neurological outcome, increased CPP, decreased ICP, decreased CAP Index, and decreased interventions to lower ICP. With a BIS ≥60 or StcO₂ ≥70, ICP and CPP are likely to be acceptable. A BIS ≥60 or StcO₂ ≥70 indicate there is a high probability of an acceptable CPP (CPP ≥60, 97.2% rate) and ICP (ICP ≤20, 90.8% rate; ICP ≤25, 97.1% rate).

Our previous investigation included 3,722 hourly observations of StcO₂ in patients with severe brain injury [9]. This study also demonstrates that StcO₂ is associated with survival and CPP in a similar patient cohort. These findings have been validated by other investigators [10]. In severe brain injury, BIS values correlate with recovery of consciousness [18], the raw EEG during barbiturate coma [19], and brain death [20]. In patients with variable degrees of brain injury, BIS correlates with positive brain CT scan and neurological outcome [21].

Future studies may determine if select patients with a BIS ≥60 or StcO₂ ≥70 can be managed without ICP monitoring. Potential candidates are blunt trauma patients with intracranial hemorrhage, GCS score 6 to 8, no need for emergency craniotomy, differentiated gray-white matter, no significant midline shift, patent basal cisterns, patent sulci, and reactive, symmetric pupils. With a BIS ≥60 or StcO₂ ≥70, an ICP monitor may not be necessary. With a BIS <60 and StcO₂ <70 an ICP monitor is indicated. Other patients who may benefit from BIS and StcO₂ monitoring without ICP monitoring are blunt trauma patients with intracranial hemorrhage, GCS score 9 to 12, and the need for mechanical ventilation and sedation.

Additional investigations may prove that a marginal ICP in blunt trauma patients with intracranial hemorrhage and GCS score 3 to 8 does not need to be lowered with BIS ≥60 or StcO₂ ≥70. Specifically, when ICP is 15 to 20 mmHg and BIS ≥60 or StcO₂ ≥70, interventions to lower ICP may be unnecessary. However, with BIS <60 and StcO₂ <70, interventions to lower ICP or increase CPP should be considered.

The CAP Index is a parameter that was identified during this study. However, no other study, to our knowledge, has described such a relationship. CAP Index is a relationship that readily classifies patients according to neurological outcomes. An elevated CAP Index indicates a modest reduction in MAP and substantial increase in ICP. When comparing the surviving and nonsurviving patients, the mean difference is much greater for the CAP Index than it is for ICP, CPP, StcO₂, and BIS. Similar relative differences are noted when comparing patients with good neurological outcome and bad outcome. An increased CAP Index is associated with death, poor neurological outcome, and increased interventions to lower ICP. CAP Index is correlated with, but not identical to, ICP, MAP, and CPP. CAP Index has an additional association with survival, good neurological outcome, and lack of need for interventions to lower ICP, independent of ICP and CPP. These findings suggest that the CAP Index is a distinct, interactive parameter. When the CAP Index is increased, there is no relationship between MAP and ICP. When there is no relationship between MAP and ICP, increasing MAP typically will not increase ICP [15, 22, 23] Thus, when the CAP Index is increased and ICP cannot be reduced, increasing MAP may improve CPP. This implication needs to be tested.

There are several study limitations. A larger group of patients needs to be evaluated to confirm the observations in this study. Severe forehead, soft tissue injury may prohibit BIS or cerebral oximetry sensor application or alter the BIS or StcO₂ values. Bilateral frontal lobe contusions may alter the StcO₂ values, thus impeding their clinical interpretation. A frontal subdural hematoma may interfere with BIS or StcO₂ values. Discharge GCS score status was included, as one of several measures, to assess ICU outcomes. Admission GCS score was 3 to 8 for all patients, indicating severe neurological impairment. A discharge GCS score of 3 to 8 would indicate relatively poor neurological outcome. A discharge GCS score of 9 to 15 would indicate an improvement and a relatively good neurological outcome, when compared to admission. Because of the above, discharge GCS score was dichotomized as a relative indication of ICU outcome. However, quality of life and Glasgow Outcome score assessment at six months may be a more relevant indication of neurological outcome. These outcomes need to be compared with post-injury BIS and StcO₂ values. The study focuses on severe traumatic brain injury. CT scan evidence of intracranial hemorrhage was a study inclusion requirement, because it suggests a history of mechanical brain trauma. Severe cognitive impairment due to mechanical brain injury can occur without intracranial hemorrhage, although this is relatively uncommon. With post-traumatic severe cognitive impairment, the absence of intracranial hemorrhage suggests that hypoxemia or shock may be the primary pathology. The study does not address patients with hypoxic encephalopathy, medical subarachnoid hemorrhage, and diffuse axonal injury. A larger group of patients needs to be studied to determine the impact of individual brain pathology on outcomes and BIS and StcO₂ values. Prospective trials need to be performed to assess the hour-to-hour treatment implications of BIS and StcO₂ values. The CAP Index, to our knowledge, has never been described in the literature. Additional investigations need to be conducted to define its therapeutic implications. Further studies are required to determine if the prognostic implications found in this study can be corroborated.

CPP, BIS, and StcO₂ monitoring are intended to assess global intracranial blood flow, regional cerebral cortical function, and local cortical oxygen extraction, respectively. The associations of BIS and StcO₂ with ICU outcomes (survival, neurological outcome, ICP, CPP, CAP Index, and interventions to lower ICP) indicate that BIS and StcO₂ are clinically discriminate parameters. The independent associations of BIS, StcO₂, and ICP or CPP with outcomes indicate that BIS, StcO₂, and ICP values are complementary. Apropos, the noninvasiveness of BIS and StcO₂ is appealing. ICP and CPP monitoring are limited by non-distinct targets and need for expertise with monitor insertion. Study findings indicate that cerebral hypoxia occurs and brain wave patterns are altered when ICP increases, CPP decreases, or CAP Index increases. BIS ≥60 or StcO₂ ≥70 suggest that patients with severe brain injury are likely to have an acceptable ICP and CPP. Future studies will define the role for BIS and StcO₂ monitoring with traumatic brain injury. They will determine if select patients with BIS ≥60 or StcO₂ ≥70 can be managed without ICP monitoring. Such investigations may prove that an ICP of 16 to 25 mmHg does not need to be lowered with BIS ≥60 or StcO₂ ≥70. An increased CAP Index is a harbinger of poor outcome. Further studies may show that, when the CAP Index is increased and ICP cannot be reduced, raising MAP will enhance CPP.