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Procrustes, the Traumatic Penumbra, and Perfusion Pressure Targets in Closed Head Injury

Menon, David K. F.R.C.A.

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THE cerebral perfusion pressure (CPP; mean arterial pressure−intracranial pressure) is a major determinant of cerebral perfusion in the injured brain. Several recent studies have attempted to provide data on optimal CPP targets within the context of protocols for the intensive care management of severe traumatic brain injury. The report by Nordström et al.1 in this issue of Anesthesiology adds to our information on this subject. Many centers use an approach based on a conceptual framework popularized by Rosner et al.2 and attempt to keep CPP above the lower limit of cerebrovascular autoregulation, which is thought to be shifted upwards following traumatic brain injury. This view has significantly influenced current thinking on this topic, and recent expert guidelines 3 have suggested that CPP be maintained above 70 mmHg. However, a different approach, first proposed by clinicians from Lund, Sweden, 4 is based on interventions aimed at reducing intracranial volume and, hence, intracranial pressure. Perhaps the largest perceived difference between the Lund approach and the Rosner et al.2 approach (and CPP targets of 70 mmHg specified in current published guidelines) is the stated willingness of the Lund group to accept CPP targets as low as 50 mmHg.
Although both of these approaches have been shown to result in good clinical outcomes, 2,5 they have never been directly compared. However, a recent randomized study by Robertson et al.6 found no benefit, in terms of the Glasgow Outcome Score, from CPP-targeted therapy (aimed at maintaining CPP above 70 mmHg) when compared with conventional intracranial pressure–targeted therapy (in which CPP was maintained above 50 mmHg). This result was attributed, at least in part, to increased cardiorespiratory complications of therapy in the CPP-targeted group. A recent commentary by Robertson 7 in Anesthesiology made a persuasive case for targeting a CPP of 60 mmHg in traumatic brain injury protocols. These results provide useful guidance on optimal CPP levels across patient populations. However, they do not address the issue of heterogeneity between or within patients, which could result in some patients, or some areas in the injured brain, benefiting from a higher (or lower) CPP. Such optimization could conceivably result in subtle improvements in neurocognitive outcome that might be missed by the Glasgow Outcome Score.
Nordström et al.1 attempt to address the first of these two issues in their report. They used microdialysis to monitor extracellular fluid metabolite concentrations from perilesional (“worse”) tissue and relatively normal (“better”) tissue in 50 patients with head injury and retrospectively investigated the relationship between CPP and extracellular fluid concentrations of lactate, pyruvate, and glucose. Extracellular fluid glucose concentrations were unrelated to sampling site and were unaffected by CPP levels. However, extracellular fluid lactate concentrations were higher in worse areas than in better areas when the CPP was greater than 70 mmHg or less than 50 mmHg. Although lactate concentrations in better areas did not vary significantly with CPP, lactate concentrations in the worse areas were significantly higher when CPP decreased to less than 50 mmHg. Lactate–pyruvate ratios generally followed these trends, but differences were less robust. The authors infer that perilesional tissues are more sensitive than normal brain tissue to reductions in CPP and do not tolerate CPP levels below 50 mmHg. They also interpret these data to support the use of the Lund protocol, with reductions in CPP to 50 mmHg if needed for intracranial pressure control.
While these results are interesting, we need to consider several issues. Clinical management in these patients was based on the Lund concept. 4,5 Although CPP was initially maintained at 60–70 mmHg, it was allowed to drop to 50 mmHg if this allowed control of intracranial pressure. Most patients received low-dose thiopental (0.5–3 mg · kg−1 · h−1) and antihypertensives (metoprolol and clonidine); 11 received dihydroergotamine to reduce cerebral blood volume. These treatment modalities and the variable (but unspecified) levels of hyperventilation that the patients received represent important confounding factors that may have been responsible, at least in part, for some of the metabolic abnormalities seen. Thus, the patients with the lowest CPP values may well have been the ones who received dihydroergotamine for intracranial pressure control or were hyperventilated to moderate hypocapnia—interventions that have either the potential 8 or the documented effect of reducing regional perfusion 9 and causing metabolic deterioration. 10 It is also important to point out that lactate concentrations in the worse areas were significantly higher than those in the better areas, even when the CPP was greater than 70 mmHg. The investigators did not explore the possibility that further increases in CPP might normalize lactate concentrations, even in perilesional regions. Finally, they did not provide information on how these intermediate physiologic end points were related to eventual clinical outcome. While the data they present do advance our understanding of pathophysiology, relating these data to local or global outcome would be an important step in establishing the role of microdialysis as a clinical monitoring tool.
Despite these caveats, the results of the study conducted by Nordström et al.1 are important because they highlight differences in pathophysiology within the injured brain and show that changes in physiology may have selective effects in vulnerable perilesional areas. This raises the possibility that we may have to tailor critical care management to prevent extension of injury to such areas. The ischemic penumbra is a concept that has long been recognized in experimental 11 and clinical stroke 12 and represents a region of tissue that is most affected by clinical management and neuroprotective interventions. These data, along with those provided by physiologic imaging studies, 9,13 make a strong case for identifying these perilesional areas as a traumatic penumbra, in which we can do the most harm or good depending on how we manage patients. Such perilesional areas are often in the vicinity of frontal and temporal contusions, in regions that have important roles in memory and executive performance. 14–16 Since much of the brain is at risk for secondary injury from physiologic insults following brain trauma, the traumatic penumbra may need to be defined physiologically rather than confined in terms of perilesional anatomy. However, regardless of the location of such tissue, improvements in outcome produced by preservation of neuronal function in these areas may be of immense importance to patients but may not result in movement along a relatively coarse, five-point Glasgow Outcome Score. Benefits from such targeted interventions will therefore need to be assessed by outcome measures with better discrimination at the higher end of the outcome spectrum; formal neuropsychologic assessment may be needed, but the extended Glasgow Outcome Score 17 is a useful step in this direction.
Finally, Nordström et al.1 may have missed an important opportunity. In an effort to assess the effect of regional pathology on local physiology, they ignored interindividual variations in their analysis and pooled data from different subjects within CPP ranges. It would have been interesting to know whether the inflection point for elevation of lactate concentrations with reductions in CPP varied between patients, allowing individual optimization of CPP values. Such variability would not be unexpected. There are good data now to show that individual patients may possess different optimal ranges of CPP for autoregulatory efficiency, 18 and that pathophysiology can change within patients over time. 19 At a more fundamental level, we know that genotype can modulate outcome in head injury, 20 although the pathophysiologic mechanisms by which such modulation occurs remain unclear.
Greek mythology tells of an innkeeper named Procrustes (or “one who stretches”), a robber in the myth of Theseus who preyed on travelers along the road to Athens. He offered his victims hospitality on a magical bed that would fit any guest. He then either stretched the guests or cut off their limbs to make them fit perfectly into the bed. Our attempts to find a unitary CPP value that fits all parts of the brain in all patients may represent a Procrustean approach, the time for which has passed. We need to try to move away from attitudes that try to shoehorn patients into a single range of CPP values, either at the lower or higher end of the spectrum of discussion (or argument!). The data from Nordström et al.1 add to the growing evidence of pathophysiologic heterogeneity between and within patients following head injury and provide support for the concept of a traumatic penumbra. The challenge is to find ways to identify such penumbral tissue, to define management approaches that best preserve it in individual patients, and to find sensitive measures that can determine whether such individualized therapy results in significant clinical benefit.
This Editorial View accompanies the following article: Nordström C-H, Reinstrup P, Xu W, Gärdenfors A, Ungerstedt U: Assessment of the lower limit for cerebral perfusion pressure in severe head injuries by bedside monitoring of regional energy metabolism. Anesthesiology 2003; 98:809–14.
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References

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2. Rosner MJ, Rosner SD, Johnson AH: Cerebral perfusion pressure: Management protocol and clinical results. J Neurosurg 1995; 83: 949–62.

3. Brain Trauma Foundation, American Association of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care: Guidelines for the management of severe head injury. J Neurotrauma 2000; 17: 507–11

4. Grände PO, Asgiersson B, Nordström CH: Physiological principles for volume regulation of a tissue enclosed in a rigid shell with application to the injured brain. J Trauma 1997; 42( suppl): S23–31.

5. Eker C, Asgiersson B, Grände PO, Schálen W, Nordström CH: Improved outcome after head injury with a therapy based on principles for brain volume regulation and improved microcirculation. Crit Care Med 1998; 26: 1881–6

6. Robertson CS, Valadka AB, Hannay HJ, Contant CF Jr, Gopinath SP, Cormio M, Uzura M, Grossman RG: Prevention of secondary insults after severe head injury. Crit Care Med 1999; 27: 2086–95

7. Robertson CS: Management of cerebral perfusion pressure after traumatic brain injury. A nesthesiology 2001; 95; 1513–7

8. Nilsson F, Messeter K, Grände PO, Rosén I, Ryding E, Nordström CH: Effects of dihydroergotamine on cerebral circulation during experimental intracranial hypertension. Acta Anaesthesiol Scand 1995; 39: 916–21

9. Coles JP, Minhas PS, Fryer TD, Smielewski P, Aigbirihio F, Donovan T, Downey SP, Williams G, Chatfield D, Matthews JC, Gupta AK, Carpenter TA, Clark JC, Pickard JD, Menon DK: Effect of hyperventilation on cerebral blood flow in traumatic head injury: Clinical relevance and monitoring correlates. Crit Care Med 2002; 30: 1950–9

10. Marion DW, Puccio A, Wiseniewski R, Kochanek P, Dixon CE, Bullian L, Carlier P: Effect of hyperventilation on extracellular concentrations of glutamate, lactate, pyruvate, and local cerebral blood flow in patients with severe traumatic brain injury. Crit Care Med 2002; 30: 2619–25

11. Ginsberg MD: Adventures in the pathophysiology of brain ischemia: Penumbra, gene expression, neuroprotection: The 2002 Thomas Willis lecture. Stroke 2003; 34: 214–23

12. Baron JC: Perfusion thresholds in human cerebral ischemia: Historical perspective and therapeutic implications. Cerebrovasc Dis 2001; 11( suppl 1): 2–8

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16. Ricker JH, Hillary FG, DeLuca J: Functionally activated brain imaging (O-15 PET and fMRI) in the study of learning and memory after traumatic brain injury. J Head Trauma Rehabil 2001; 16: 191–205

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18. Steiner LA, Czosnyka M, Piechnik SK, Smielewski P, Chatfield D, Menon DK, Pickard JD: Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Crit Care Med 2002; 30: 733–8

19. Martin NA, Patwardhan RV, Alexander MJ, Africk CZ, Lee JH, Shalmon E, Hovda DA, Becker DP: Characterization of cerebral hemodynamic phases following severe head trauma: Hypoperfusion, hyperemia, and vasospasm. J Neurosurg 1997; 87: 9–19

20. Teasdale GM, Nicoll JA, Murray G, Fiddes M: Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 1997; 350: 1069–71

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