Low central venous saturation predicts poor outcome in patients with brain injury after major trauma: a prospective observational study

Background Continuous monitoring of central venous oxygen saturation (ScvO2) has been proposed as a prognostic indicator in several pathological conditions, including cardiac diseases, sepsis, trauma. To our knowledge, no studies have evaluated ScvO2 in polytraumatized patients with brain injury so far. Thus, the aim of the present study was to assess the prognostic role of ScvO2 monitoring during first 24 hours after trauma in this patients' population. Methods This prospective, non-controlled study, carried out between April 2006 and March 2008, was performed in a higher level Trauma Center in Florence (Italy). In the study period, 121 patients affected by major brain injury after major trauma were recruited. Inclusion criteria were: 1. Glasgow Coma Scale (GCS) score ≤ 13; 2. an Injury Severity Score (ISS) ≥ 15. Exclusion criteria included: 1. pregnancy; 2. age < 14 years; 3. isolated head trauma; 4. death within the first 24 hours from the event; 5. the lack of ScvO2 monitoring within 2 hours from the trauma. Demographic and clinical data were collected, including Abbreviated Injury Scale (AIS), Injury Severity Score (ISS), Simplified Acute Physiologic Score II (SAPS II), Marshall score. The worst values of lactate and ScvO2 within the first 24 hours from trauma, ICU length of stay (LOS), and 28-day mortality were recorded. Results Patients who deceased within 28 days showed higher age (53 ± 16.6 vs 43.8 ± 19.6, P = 0.043), ISS core (39.3 ± 14 vs 30.3 ± 10.1, P < 0.001), AIS score for head/neck (4.5 ± 0.7 vs 3.4 ± 1.2, P = 0.001), SAPS II score (51.3 ± 14.1 vs 42.5 ± 15, P = 0.014), Marshall Score (3.5 ± 0.7 vs 2.3 ± 0.7, P < 0.001) and arterial lactate concentration (3.3 ± 1.8 vs 6.7 ± 4.2, P < 0.001), than survived patients, whereas ScvO2 resulted significantly lower (66.7% ± 11.9 vs 70.1% ± 8.9 vs, respectively; P = 0.046). Patients with ScvO2 values ≤ 65% also showed higher 28-days mortality rate (31.3% vs 13.5%, P = 0.034), ICU LOS (28.5 ± 15.2 vs 16.6 ± 13.8, P < 0.001), and total hospital LOS (45.1 ± 20.8 vs 33.2 ± 24, P = 0.046) than patients with ScvO2 > 65%. Conclusion ScvO2 value less than 65%, measured in the first 24 hours after admission in patients with major trauma and head injury, was associated with higher mortality and prolonged hospitalization.

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Background
Organ and tissue damages caused by a trauma impact lead to the development of systemic inflammatory response syndrome (SIRS) [1]. The local and systemic release of inflammation mediators produces oxidative stress, capillary leakage, microcirculatory disturbances, metabolic alteration, imbalance of pro-and anti-inflammatory mechanisms, ischaemia/reperfusion injury, coagulation disturbances [1]. In major trauma, occult tissue hypoperfusion within the first 24 hours after event precedes multiple organ dysfunction syndrome (MODS) [2]. Despite the unquestionable usefulness of routinely monitoring of hemodynamic parameters, such as arterial lactate, central venous pressure, blood pressure, heart rate, urinary volume, hypoxia may exist despite normal clinical values [3]. Continuous monitoring of central venous oxygen saturation (ScvO 2 ) has been proposed as an indicator of tissue hypoperfusion. Although the reliability of ScvO 2 , compared with mixed venous oxygen saturation (SvO 2 ), is still under discussion, particularly under shock conditions [3], the prognostic importance of low level (≤ 65%) of ScvO 2 has been highlighted in severe sepsis [4,5], myocardial infarction [6], cardiac failure [7], and trauma [8]. Moreover, ScvO 2 can be easily monitored with a central venous line, whereas SvO 2 requires a pulmonary artery catheterization.
In a recent investigation about the cause of death in trauma Soreige K et al. [9] found a high percentage of head trauma (67%) and concluded that focus on brain injuries prevention is imperative.
To our knowledge, no studies have evaluated ScvO 2 in patients affected by brain injury after major trauma so far. Thus, the aim of the present investigations was to assess the useful of an early monitoring (first 24 hours) of ScvO 2 in patients with major trauma and head injury.

Data collection
The study population was recruited from the Intensive Care Unit (ICU) of Careggi Teaching Hospital (Florence, Italy) from 1st April 2006 to 31st March 2008. The Careggi Teaching Hospital is an a university-affiliated tertiary care hospital of Tuscany (IT) and acts as the provincial higher level trauma center for trauma. The ICU is a 10-single bed multidisciplinary medical/surgical/trauma unit that cares primarily patients of Emergency Department.
Patients were treated according to international standard care [10] and to Advanced Trauma Life Support guide lines (see Additional file 1), and were hemodynamically stabilized according to vital signs such as heart rate, blood pressure, and central venous pressure. Other parameters considered in the evaluation of severity of hypovolemia were the need for vasoactive drugs after hemodynamic resuscitation and the number of blood units administered. Inclusion criteria were: 1. admission diagnosis for major trauma with head injury; 2. a Glasgow Coma Scale (GCS) score ≤ 13, evaluated in the pre-hospital setting before sedation; 3. an Injury Severity Score (ISS) ≥ 15; 4. Exclusion criteria included: 1. pregnancy; 2. age < 14 years; 3. isolated head trauma; 4. death within the first 24 hours from the event; 5. the lack of ScvO 2 monitoring within 2 hours from the trauma. This prospective observational study, followed the principles of the Helsinki declaration and national ethical guidelines. The study was authorized by the Local Scientific committee and the Local Ethic Committee, which waved the need of the informed consent because it did not modify the therapeutic approach provided by the current guide lines and internal protocols.
Patients' demographic and clinical characteristics were extracted from institutional ICU-database (software: File-Maker Pro 5.5v2, FileMaker, Inc, USA). All data have been collected prospectively by two trained data collectors. Patients has been anonymized, thus privacy was guarantee. Severity of disease was estimated by the Simplified Acute Physiology Score II (SAPS II) [11], a gravity score validated in 1993, submitted to a recent revision [12] (whose score is easily calculable on the site http:// www.sfar.org/scores2/saps2.html), GCS, ISS, and AIS. The severity of the intracranial lesions was evaluated by the Marshall radiological score [13] (table 1) from the first CT-scan performed at hospital admission. Continuous monitoring of ScvO 2 was performed with Vigileo system (Edwards Lifesciences, Irvine, California, USA). Central catheter was placed within the first two hours after admission in all patients enrolled. During the first 24 hours after trauma, both minimum value of ScvO 2 , measured for at least 15 minutes during the first 24 hours after trauma, and highest arterial lactate concentration were recorded. The data collectors verified that these values were not affected by episodic hypoxia during tracheal tube change, fibrobronchoscopy, occasional hypotension.

Statistical Analysis
All analyses were performed using SPSS 10.0 statistical software package (SPSS, Chicago, Illinois, USA). Student's t-test was used for the numerical data, and two-tailed P value was considered significant if less than 0.05. Categorical data have been analysed with Fisher's exact test, with two-sided P significant if < 0.05. The cut-off values have been chosen based on statistically significant mean values of subgroups analysis. Multiple logistic regression has been performed on demographic and clinical parameters. A value of < 0.05 was considered significant.

Overall population
In the study period, 121 patients met the inclusion criteria. 255 patients were admitted to the Emergency Room with ISS > 15 and GCS < 13; of these 21 died in the first 24 hours, 63 did not confirm a low GCS at the secondary evaluation and, in 50 of these the insertion of venous central catheter in the first 2 hours from trauma was not possible. Overall patients' demographic and clinical characteristics and comparison between 28-days survived and deceased patients are summarised in Table 2. Patients enrolled had a prevalence of head/neck and chest injury, as resulted from AIS score ( Table 2). Male sex was predominant in both groups and represents 78% of overall population. This gender prevalence is in accordance on what usually observed in our clinical practice. On average, deceased patients showed a significant higher age (53 ± 16.6 vs 43.8 ± 19.6, P = 0.043), ISS core (39.3 ± 14 vs 30.3 ± 10.1, P < 0.001), AIS score for head/neck (4.5 ± 0.7 vs 3.4 ± 1.2, P = 0.001), SAPS II score (51.3 ± 14.1 vs 42.5 ± 15, P = 0.014), and Marshall Score (3.5 ± 0.7 vs 2.3 ± 0.7, P < 0.001), if compared with survived patients. Consistently with these observations, survived and deceased patients resulted significantly different in arterial lactate concentration (3.3 ± 1.8 vs 6.7 ± 4.2, respectively; P < 0.001) and ScvO 2 (70.1% ± 8.9 vs 66.7% ± 11.9, respectively; P = 0.046) ( Table 2).

Mortality
The observed overall 28-days mortality rate was 18.2%. According with the differences between survived and deceased patients, contingency analysis showed that the The score is based on the severity of intracranial lesions identified at head CT scan  (Table 3). A multiple regression analysis performed on parameters with a higher correlation with 28-days mortality showed that variables which mostly contributed to the prediction of mortality were Marshall score (P = 0.001) and lactate concentration (P = 0.002). The calculation of concordance rate between two multiple regression analysis showed that adding ScvO 2 to the other variables considered (age, AIS for head/neck, ISS, SAPS II, Marshall score and lactate concentration), raised the rate of correct predictions of 1% (from 86.6% to 87.6%).

Discussion
The aim of the present investigation was to assess the role of early ScvO 2 monitoring in trauma patients with associated head injury. We assumed that a persistent low ScvO 2 could be the expression of the dangerous effects of generalized and, concomitant, brain hypoperfusion in patients with brain injury and major trauma and, therefore, that it could predict a worst evolution.
The prognostic importance of low level (≤ 65%) of ScvO 2 has been emphasized in severe sepsis [4,5], myocardial infarction [6], and cardiac failure [7]. The significance of ScvO 2 in patients with major trauma has been previously reported in 26 injured patients [8]. In their investigation, Scalea and co-workers found that ScvO 2 measurement was a trustworthy parameter to estimate blood loss, especially in patients who showed an ScvO 2 below 65% despite stable clinical signs [8]. In opposition with this observation, a subsequent study did not confirm the reliability of ScvO 2 as indicator of blood loss in 40 trauma patients [14]. According with Scalea et al., the lack of linear correlation between low ScvO 2 and stable clinical signs has been also corroborated by Rady and colleagues in a nonrandomized study on sixteen patients presenting to the emergency department in shock conditions, who presented ScvO 2 below 65% in almost 50% of cases, despite the hemodynamic stabilization [5].
The ScvO 2 cut-off value of ≤ 65% has been chosen in the present investigation based on existing literature [5,8,14] and on the average we found in our patients deceased at 28 days (66.7%, Table 2). The main finding of this study was the relationship between an ScvO 2 values ≤ 65%, for at least 15 minutes during the first 24 hours from trauma, and mortality rates (Table 4). It must be noted that in the group with lower ScvO 2 also injury scores and lactate levels were worst. In regard, the absolute significance of ScvO 2 in predicting mortality in the multivariate analysis was lower than Marshall score and lactate levels in our investigation. However, the inclusion of ScvO 2 in a multiple regression model showed that mortality prediction can be improved from 86.6% to 87.6%: this improvement, whereas not ample, could be relevant in the day to day clinical practice. In consideration of our results, ScvO 2 should be never considered as a substitute of lactate monitoring or injury scores in predicting outcome. In addition to these observations, patients with ScvO 2 values > 65% discharged alive from ICU, showed significantly reduction in both ICU and total hospital LOS (Table 4). Our findings are partially in accordance with a recent study performed on 96 critically ill patients admitted in a multidisciplinary ICU, in which an ScvO 2 value below 60% at admission was related with high mortality rate but not with a prolonged ICU LOS [15]. On regard, it must be considered that the study of Bracht and co-workers was performed on unselected critically ill patients, with a not specified number of central nervous system injured patients (less than 30% of total patients enrolled), whereas our population included polytraumatized patients with head injury. In our study, the association between low level of ScvO 2 and ICU/hospital LOS appeared strong; however, this finding could be also related with the differences in age and injuries observed in the two subgroups ( Table 4).
The most numerous and extensive studies on ScvO 2 optimization have been performed on septic patients. To our knowledge, no study has investigated the usefulness of ScvO 2 monitoring to guide hemodynamic stabilization and to improve outcome in patients with major trauma [3]. The pathogenic changes following major trauma include SIRS, oxidative stress, capillary leakage, metabolic alterations, and diffuse tissue hypoxia as a result of circulatory abnormalities [1]. This pathophysiological process is somehow very similar with what observed in septic patients, although sepsis presents a different aetiology, evolution and possibility to be treated with antibiosis. In our investigation, ScvO 2 was not included as a target parameter for hemodynamic optimization, so none can be gathered from our data on application of early-goal directed therapy protocol in major trauma. Nevertheless, considering the good evidence in patients with severe sepsis/septic shock, the use of ScvO 2 to guide hemodynamic optimization in polytraumatized patients would merit to be adequately investigated.
Limits of present findings merit considerations. 1) We did not included data on fluids administration in the first 24 hours, brain damages evolutions, intracranial pressure, and their relationship with ScvO 2 levels. Second, the exclusion of patients who died in the first 24 hours from the study protocol might be a potential bias. The reason of this choice depended from our goal to investigate the role of ScvO 2 in the first 24 hours, which are considered critical in the evolution of MODS in polytrauma [2]. Third, we were not blinded for the primary end points (but in an emergency setting is not so easy), but the collection of data was made by an external investigator that was blind for the end points. Finally, the lack of a control group with a pulmonary artery catheter with SvO 2 monitoring did not allow a comparison between ScvO 2 and SvO 2 , although previous studies showed that changes of both values proceed in a parallel manner, even under shock conditions [3,16].

Conclusion
In conclusion, an early monitoring of ScvO 2 could aid to predict the outcome in patients with major trauma and head injury. In particular, we found that a value less than 65%, measured during the first 24 hours after admission, was associated with higher mortality rate and prolonged ICU and hospital LOS. So, our results seem to suggest the use of ScvO 2 as a target of resuscitation in patients with brain injury after major trauma. The validation of ScvO 2 in monitoring of cerebral metabolism and as a target for hemodynamic resuscitation in polytraumatized patients remains to be investigated.