Journal Club
Neurosurgery's Journal Club extends the existing practice of Journal Club common to all neurosurgical training programs in which residents and fellows critically review published articles under the guidance of faculty. Runner-up submissions in the competition are published here on a quarterly basis.

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Tuesday, January 29, 2013

Journal Club Runner-Up: University of Illinois Peoria
Derek Martinez, MD1 Tobias Mattei, MD2

1Department of Neurosurgery, University of Illinois at Peoria, Peoria, IL; 2 Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, Illinois, USA

Journal Club Article: Oddo M, Levine J, Mackenzie L, et al. Brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. Neurosurgery. 2011;69:1037-1045

Significance/context and importance of the study

Traumatic Brain Injury (TBI) is a prevalent cause of morbidity and mortality in our society with an annual incidence around 558 per 100,000 persons and with the heaviest burden carried by youth and young adults.1 TBI are usually complicated by the secondary injury that occurs in the aftermath of the initial insult and, therefore, at least theoretically, monitoring and acting upon brain tissue hypoxia may have an important impact upon the patients’ long-term prognosis.

Although TBI guidelines address brain tissue oxygenation (PbtO2) the current standard of care in the majority of intensive care units is still based upon intracranial pressure (ICP) and cerebral perfusion pressure (CPP).2 However, these guidelines are limited by a relative paucity of rigorous studies and therefore only Class II or Class III data is available. Nevertheless, animal studies have suggested that brain tissue hypoxia exacerbates neurologic deficit, neuroinflammation and cerebral metabolism after diffuse traumatic brain injury.3 Furthermore clinical studies have suggested that combined ICP/CPP- and PbtO2-based therapy may be associated with better outcome after severe TBI than ICP/CPP-based therapy alone.4 It is therefore reasonable to pursue clinical evidence for the utility of hypoxia as an indicator and treatment guide.

Currently, widely employed methods for ICP monitoring include intraparenchymal pressure monitors and extra-ventricular drainage devices. Adjunct methods, such as jugular venous sampling and tissue microdialysis, have also been used in the setting of severe TBI but the evidence supporting therapy based on such parameters is scarce and, therefore, their use is still not yet widespread in general neurosurgical practice. Due to the high prevalence of TBI as well as the high burden of associated morbidity and mortality clinical investigation which provides data to support best practices as well as introduce viable new monitoring devices are very welcome in the neuro-critical care literature.

Originality of the work

The group presenting this study is well known in the neurosurgical critical care literature for their contributions to TBI research both at the basic science and clinical levels. They have already presented several studies related to monitoring parameters commonly used in the acute care of TBI patients. In the current article they present a retrospective, short-term comparison of TBI treatment with monitoring of ICP, CCP and PbtO2. A prospectively obtained database of TBI patients from a single institution over a timeframe of several years provided the source information for their analysis.

Appropriateness of the study design or experimental approach

Although the study suffers from the limitations of a retrospective review of data previously obtained in a non-randomized fashion, it accomplishes the proposed goal of evaluating the use of PbtO2 independent from ICP and CPP as a predictor of patient outcome. It does not confirm that PbtO2 is necessarily a clinically significant guide for therapy in TBI. In the methods section the authors describe a treatment protocol that is likely similar to many of those currently in use by critical care units. Most TBI patients, especially in the acute setting, have frequent monitoring of several physiological parameters including ventilator/respiratory status, hemoglobin, electrolytes, and other systemic derangements. Therefore, although the authors were able demonstrate a relationship between PbtO2 therapy and outcome they could not demonstrate that PbtO2 directed therapy was the cause of better outcomes. In fact, a more robust study setting and a multivariate analysis taking in account all the other aforementioned factors would be necessary to accomplish the latter goal.

Treatment was not blinded to PbtO2. Nevertheless a blinded study would only be able to identify the predictive nature of tissue hypoxia and not the association between hypoxia-guided therapy and outcomes. Another possible drawback of the study is that TBI patients comprise a very heterogeneous group. Although the authors were careful to control for confounding variables such as radiographic abnormalities at presentation, age, health status, even patients with similar epidemiological characteristics may have very different injury mechanism as well as individual variations in the response to such injuries.

Adequacy of experimental techniques

The treatment techniques described in the paper are in accordance with the current practice in the general neuro-critical care community. In particular, placement of the Licox monitor was similar to that described in other previous studies. The intensive care unit treatment protocols for TBI used in the study have also been derived from standard guidelines. They are part of the standard practice in the vast majority of critical care units dealing with TBI patient and thus the methods and results of this study can more easily be tested and tried by other groups.

Soundness of conclusions and interpretation

The authors recognized the limitations of the study design, such as its retrospective character, and keep their conclusions within the confines of what the data demonstrates. Most significantly, the authors acknowledge that PbtO2 monitoring may not be entirely cost-effective or provide further benefit in comparison to the current ICP/CPP-based protocols. However, because they found a relationship between brain hypoxia and poor short-term outcome after severe TBI independently of elevated ICP, low CPP, and injury severity, the authors suggest that further investigation regarding PbtO2-guided-therapy is warranted. This is a reasonable conclusion given not only their data but also the current state-of-the-art TBI guidelines in which every recommendation should highlight the underlying level of evidence which supports it.

Relevance of discussion

The discussion is well thought out and presented. The authors address the macroscopic picture of TBI monitoring and discuss their study design, limitations, as well as their results in the context of current literature data. The authors also clearly enumerate the limitations of their study and describe how such limitations may affect the presented results.

Importantly, the authors recognize that it still remains to be proven if the patients with low PbtO2 who received cause-correcting treatment would have had the same treatment even without tissue oxygenation monitoring. For example, several causes of low tissue oxygenation, such as decreased hemoglobin and poor respiratory status, can be optimized as part of a standard treatment regimen without the need of secondary monitoring to low PbtO2. Possible exceptions include patients who are treated in accordance with such treatment protocols but despite apparent optimization of clinical parameters have decrease brain tissue oxygenation. The authors identify the salient point that patients who continue to have hypoxia in the absence of other abnormal signs such as ICP/CPP problems and who would be identified and subsequently treated on the basis of PbtO2 monitoring need to be studied in greater detail.

Clarity of writing, strength and organization of the paper

The figure, table headings and captions are concise and the body text is clear. There are no significant syntax or style drawbacks that detract from the content. The technical descriptions are readily understandable and, therefore, easily reproduced.

The article is organized logically and each portion of the results section is explained clearly. The discussion is also well organized and the self-critique of the study is enumerated and presented in a straightforward manner.

Economy of Words

The authors employ appropriate reminders of key-points without re-hashing the content unnecessarily. Abbreviations are well used and are not too numerous. Overall, each section of the paper is given sufficient but not excessive attention.

Relevance, accuracy and completeness bibliography

The bibliography is well constituted and references studies that provide a basis for the current article and support future research in the same vein.

Number and quality of figures, tables and illustrations

Overall the figures and tables are well laid out and accessible for the reader. In particular, Figures 1 and 2 and Table 3 stand out as key elements for understanding the content of the article.

Figure 1 is an interesting graphical depiction of their method to quantify the variation of physiologic variables from the normal ranges. It enhances the textual description of their use of the linear interpolation method to measure departure from the norm.

Figure 2 is well designed and clearly demonstrates the treated causes of hypoxia in the studied patients.

Table 3 is very useful for grouping and highlighting the overlap between ICP and CPP parameters and PbtO2. One critique is the lack of subset data related to Table 3. A breakdown of the 9 and 12 patients that demonstrated oxygenation issues despite purportedly normal ICP and CPP would have been useful to augment the discussion. The premise of the article hinges on patients in these subgroups. They are also the patients for whom PbtO2 monitoring had the potential to identify as at risk for injury and thus possibly benefit the most. A description of their condition and clinical course would help the reader to ascertain why these patients are different from those in the other groups. In other words, do these patients have other factors in common with each other but not with the remainder of the patients that could be potential targets of intervention or are they simply patients that do not respond to conventional treatment based on ICP/CPP?

Future/next steps

With an eye toward class 1 evidence for the questions that the authors aim to address (the relationship of hypoxia and patient outcomes as well as the role of PbtO2-guided therapy), a prospective randomized controlled trial would be the ideal design for a future study. This may prove difficult to achieve in the setting of TBI as evidenced by the current lack of randomized studies comparing adjunct PbtO2 –based therapy and stand alone ICP/CPP based therapy.

As ICP and CPP are established modalities for TBI management it is unlikely that PbtO2-monitoring will replace ICP monitoring, at least not in the near future. Nevertheless it may become an increasingly important complementary modality.

The true value of PbtO2 monitoring will be demonstrated if:

1) Future studies show that it enables clinicians to reliably identify patients susceptible to secondary injury who would not otherwise be suspected with current monitoring methods;

2) Future studies prove that a combination of ICP/CPP and PbtO2-directed therapy results in better long-term outcomes than ICP/CPP-guided therapy alone (the current standard of care).

If these two points can be addressed with strong Class I and II evidence the treatment of TBI patients will be well served by the use brain tissue oxygen monitoring. Continued funding and research is necessary to improve our understanding of traumatic brain injury and to improve our clinical treatment efficacy.


1 Leibson CL, Brown AW, Hall Long K, Ransom JE, Mandrekar J, Osler TM, Malec JF. Medical Care Costs Associated with Traumatic Brain Injury over the Full Spectrum of Disease: A Controlled Population-Based Study. J Neurotrauma. 2012 Apr 26. [Epub ahead of print]

2 Bullock MR, Chesnut R, Ghajar J, Gordon D, Hartl R, Newell DW, Servadei F, Walters BC, Wilberger J; Surgical Management of Traumatic Brain Injury Author Group. Neurosurgery. 2006 Mar;58(3 Suppl):S25-46; discussion Si-iv. Review.

3 Yan EB, Hellewell SC, Bellander BM, Agyapomaa DA, Morganti-Kossmann MC. J Post-traumatic hypoxia exacerbates neurological deficit, neuroinflammation and cerebral metabolism in rats with diffuse traumatic brain injury. Neuroinflammation. 2011 Oct 28;8:147.

4 Nangunoori R, Maloney-Wilensky E, Stiefel M, Park S, Andrew Kofke W, Levine JM, Yang W, Le Roux PD. Brain Tissue Oxygen-Based Therapy and Outcome After Severe Traumatic Brain Injury: A Systematic Literature Review. Neurocrit Care. 2011 Aug 16. [Epub ahead of print]