Managing Ischemic/Hypoxic Brain InsultsDavid S. Warner, M.D. Durham, North Carolina
311Page 1
Introduction
The perioperative environment poses inherent risk for insufficient metabolic substrate delivery to brain.Although preoperative diagnostics, monitoring, and surgical advances have undoubtedly reduced the frequency perioperative brain injury, such injuries still occur.In the perioperative environment, we have few completed randomized prospective clinical trials withsufficient statistical power to provide solid recommendations regarding appropriate prevention and treatment of perioperative hypoxic/ischemic injuries. The few studies that do exist have focused on carefully selected patient populations. Although this design provides scientific validity, it leaves open large questions regarding theappropriateness of extending the conclusions drawn from such studies to other patient populations, some of whichare too sporadic or uncommon to ever be subjected to formal analysis of intervention efficacy.When we think about preventing and treating ischemic brain injury, a great deal of our practice is basedinferences drawn from laboratory research. It is noteworthy that most phenomena widely recognized to occur inhuman brain sustaining ischemic/hypoxic insults, in fact, were first described in laboratory animals. These phenomena include accumulation of extracellular excitatory neurotransmitters, delayed neuronal necrosis, selectivevulnerability, apoptosis, ischemic penumbra, free radical injury, delayed hypoperfusion, pharmacologic effects of anesthetics on the electroencephalogram, cerebral blood flow, metabolic rate, etc. Such interspecies concordancelikely provides validity to use of laboratory models to study human disease. At the same time, many apparently promising interventions, first described in the laboratory, have later failed to translate to efficacy in human disease.This is likely attributable to both the models and human trial design. For example, efficacy from intervention instroke patients typically has been measured several months after the treatment was given.
1
In contrast, mostlaboratory studies define outcome only a few days after treatment. It has become clear that ischemic and traumatic brain injury (TBI) are active process, which proceed for weeks to months following the initial insult. Thus, short-term outcome laboratory studies may not predict the final damage examined in human trials. At the same time, mosthuman trials have been initiated before sufficient laboratory evidence had been accumulated to define appropriatedosing strategies, effects of age and gender, bioavailability, toxicity, etc. Thus, it is plausible that many failures inhuman trials could have been avoided had more extensive preclinical evaluation of the compound been performed.It is reported that patients undergoing general surgical procedures have an incidence of stroke that modestlyexceeds that of non-hospitalized patients.
2
The perioperative environment presents a complex circumstance for definition of causality and interventional efficacy. This is partly attributable to the anesthetic state, which while potentially protective, also masks brain ischemia that might otherwise be functionally evident in the awakeindividual. Although monitoring evoked potentials and the electroencephalogram can provide on-line information,the specificity of these monitors is limited and efficacy of these monitors has not been proven. It is also of importance to note that the majority of perioperative strokes do not manifest until days or weeks postoperatively.
3,4
This implicates causality that is either triggered by intraoperative events (e.g., coagulation disorders) or factorsassociated with recovery (e.g., atrial fibrillation, dehydration). Risk factors for perioperative stroke have beenvariously defined but are more likely to be associated with co-morbidities (e.g., peripheral vascular disease, prior stroke, COPD) than intraoperative events.
4,5
Of note, there remains lack of definitive association between incidenceof perioperative stroke and transient intraoperative hypotensive events,
4,5
which are often pointed to as a smokinggun by consultants not familiar with the literature.Given the relatively low incidence of perioperative stroke (outside high risk vascular procedures), the lack of a definitive etiology, and delayed onset of diagnosis, it is unlikely that we will obtain the sort of human clinicaltrials necessary to provide population-specific evidence-based recommendations for management of perioperativeischemic/hypoxic brain injury. Consequently, the balance of this discussion will draw heavily upon inferencesdrawn from other patient populations and the laboratory.
Oxygen
It is tempting to default to a recommendation of “keep red blood moving”. Although this is intuitivelyobvious, there remains debate regarding FIO
2
management. Theoretically, hyperoxygenation could potentiate freeradical formation and tissue injury. However, rats subjected to normobaric hyperoxia during and/or after a focalischemic insult, in fact, had reduced infarct size.
6
Furthermore, hyperbaric O
2
(2.5 atm) begun immediately after reperfusion improves outcome from a similar insult in rats.
7
Conversely, dogs exposed to cardiac arrest andresuscitation with 100% O
2
had more severe injury in the selectively vulnerable hippocampus than those resuscitatedwith room air.
8
This was associated with free radical injury to pyruvate dehydrogenase inhibiting aerobicglycolysis. Hyperoxic resuscitation has been reported to have similar adverse effects in newborn humans.
9
Further
311Page 2research is needed but it is plausible that benefits/risks of hyperoxia may be dependent upon the type of ischemic/hypoxic insult being treated and upon the timing of therapy. With lack of better evidence, use of pulseoximetry to optimize hemoglobin saturation may provide the safest compromise when deciding upon oxygen doseduring resuscitation.
Carbon Dioxide
One of the brain’s most primitive and resilient mechanisms of blood flow regulation is responsivity toarterial carbon dioxide concentration (PaCO
2
). Because reduced PaCO
2
is associated with reduced cerebral bloodflow (CBF), and because reduced CBF is associated with reduced intracranial pressure (ICP), it had been common practice to treat intracranial hypertension with hypocapnia. This was extended to the operating room, particularly inthe place of space-occupying lesions. Further, some drugs such as volatile anesthetics can increase ICP, but this isattenuated with hyperventilation.
10
Although these points of logic appear to provide sound rationale for employinghyperventilation in brain-injured patients, the logic ignores a potentially important issue. If the dilemma presented by intracranial hypertension is decreased perfusion pressure, potentially severe enough to render tissue ischemic,does it make sense to treat ischemia with a vasoconstrictive intervention such as hyperventilation? This plausiblycould, in fact, exacerbate ischemia. This question remained unresolved until recently when proton emissiontomography was used to study patients with TBI. Reducing PaCO
2
from 35-40 mm Hg to only 30 mm Hg caused a2.5-fold increase in the volume of brain having flow values <10 ml/100gm/min.
11
This is consistent with the only prospective trial of hyperventilation on TBI outcome which observed a decreased number of patients with resultantgood or moderate disability when chronic hyperventilation was employed.
12
Information such as this has causedthe Brain Trauma Foundation (American Association of Neurological Surgeons) to advise that use of hyperventilation “should be avoided during the first 5 days after severe TBI and particularly during the first 24hours”.
13
It remains unresolved whether acute hyperventilation provides improved outcome value for pendingtranstentorial herniation or when rapid surgical decompression of a hematoma (e.g., epidural) is anticipated. Withinthe context of focal ischemic stroke, clinical trials have found no benefit from induced hypocapnia,
14,15
althoughhyperventilation is still sometimes employed in cases of refractory brain edema. Use of hyperventilation duringcardiopulmonary resuscitation may serve to increase mean intrathoracic pressure thereby decreasing perfusion pressure and is not advocated.
16
Overall, hyperventilation appears to offer greater opportunity to worsen rather than improve outcome froma cerebral ischemic insult. Monitoring end-tidal CO
2
and PaCO
2
can provide information necessary to maintainnormocapnia.
Blood Glucose
Critical substrates for aerobic glycolysis include oxygen and glucose, neither of which the brain maintainsin meaningful reserve. In the face of oxygen deprivation, the brain converts to aerobic glycolysis. Althoughincreased glucose concentrations would seem advantageous to support this survival mechanism of ATP production,many laboratory and clinical studies have found this not to be true. The mechanism by which hyperglycemiaaugments ischemic brain injury remains controversial. Substantial evidence indicates that intracellular lacticacidosis inhibits ionic balance and enzymatic function. Hyperglycemia also promotes recruitment of inflammatorycells, free radical formation, and endothelial cell dysfunction.
In vitro
research has suggested that hyperglycemia-induced glucocorticoid release contributes to injury although this has been questioned with
in vivo
studies.
17
Regardless of mechanism, even modest increases in blood glucose prior to or during an ischemic insult persistentlyworsen outcome in humans and laboratory models. There is increasing evidence that treatment with insulin to provide euglycemia improves clinical outcome in adult stroke.
18
The threshold values that would trigger suchintervention have not been adequately defined. In rats, a plasma glucose threshold of approximately 180 mg/dl wasnecessary to induce an adverse effect in ischemic brain.
19
In contrast, Lanier et al.
20
found intravenous glucose, inan amount insufficient to cause appreciable changes in plasma glucose concentration, was sufficient to markedlyworsen outcome from complete cerebral ischemia in primates. It has been documented that regulation of plasmaglucose below 140 mg/dl
21
or blood glucose within 90-100 mg/dl
22
substantially reduced mortality in critical care patients. Thus, different targets for insulin-induced glucose regulation could be argued for in patients withischemic/hypoxic injury. Of note, in rats overtreated with insulin following a focal ischemic insult, hypoglycemiaworsened outcome.
23
The above data, while not specific to the perioperative patient, provide sufficient evidence that blood or plasma glucose should be monitored in the acute phase of brain injury. Evidence also suggests thattreatment of hyperglycemia with insulin to establish a euglycemic state may improve outcome.
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Temperature
An interesting article was published in 1959.
24
This work occurred in the early days of development of hypothermia as a clinical neuroprotective strategy. The study retrospectively examined a series of 27 patients whoendured perioperative cardiac arrest. In the first 15 patients, no attempt was made to induce hypothermia. In thefinal 12 patients surface cooling and pharmacologic agents were used to reduce temperature to 31-32
o
C. Amongst patients for whom restoration of spontaneous circulation was achieved, mortality was substantially reduced in thosetreated with sustained hypothermia. This study is cited as interesting historical anecdote. The work was not prospective, randomized, or double-blinded with respect to defining outcome. Perhaps for this reason it receivedlittle interest until recently when two prospective, randomized, double-blinded trials were reported in which patientssustaining out-of-hospital ventricular fibrillation cardiac arrest were treated with induced hypothermia or normothermia.
25,26
Both studies identified efficacy for hypothermic intervention. It is critical to note that bothstudies maintained hypothermia for at least 12 hrs. It also is of note that in neither study did hypothermic therapyincrease the number of persistently vegetative survivors. These startling positive results represent a full circle of asuccessful series of preclinical laboratory trials that provided a rationale basis for the human trial study designs. TheAmerican Heart Association and the International Liaison Committee on Resuscitation have both endorsed use of induced hypothermia in this patient population.
27,28
These results are startling because they follow in the wake of many studies in which post-ischemic intervention has failed to improve outcome. The hypothermia studies,however, prove that such a goal is possible. This has been echoed by 2 recent reports where induced-hypothermiawas applied to infants after peripartum hypoxic-ischemic brain insults.
29,30
Both studies found benefit.It also has become apparent that hypothermia is not a panacea. For example, the out-of-hospital trialallowed computation of the efficacy of treatment. Seven patients would require hypothermic treatment to prevent 1death.
25
Furthermore, hypothermia has not been found effective in the circumstance of intracranial cerebralaneurysm clipping or acute TBI.
31,32
Insufficient evidence is available to draw conclusions with respect to focalischemic stroke. This provides a quandary to the practitioner who faces patients that do not categorically meet theinclusion criteria used for the above studies. For example, there is no prospective data is available for the patientwho sustains loss of airway or delayed detection of respiratory arrest in the operating room or recovery room thatresults in cardiac arrest. However, because these complications bear considerable neurologic similarity to that of out-of-hospital cardiac arrest, it is rationale to consider rapid induction of sustained hypothermia upon restoration of spontaneous circulation should the patient remain comatose.There also is considerable evidence that hyperthermia is adverse to the post-ischemic brain. Spontaneous post-ischemic hyperthermia is common. In animals, intra-ischemic or even delayed post-ischemic hyperthermiadramatically worsens outcome. Spontaneous hyperthermia has also been associated with poor outcome in humans.These facts provide sufficient evidence to advocate frequent temperature monitoring in patients with cerebral injury(and those at risk for cerebral injury). Minimally, aggressive intervention to obtain normothermia should beconsidered.
Volatile Anesthetics
Volatile anesthetics have been found to provide numerous potentially beneficial effects on ischemic brainincluding regulation of intracellular calcium concentration, inhibition of cortical spontaneous depolarizations,reduction of metabolic rate, and potentiation of inhibitory neurotransmission. Laboratory studies have providedmixed results concerning efficacy, although most studies employing strict control of physiologic parameters haveshown substantial benefit. The limits of volatile anesthetic neuroprotection are incompletely defined. Most insultsstudied in the laboratory are severe and may not reflect specific clinical scenarios. It is postulated that as theseverity of the insult increases, efficacy of volatile anesthetics may decrease. While this makes common sense,there is not yet data to support this contention. There are no human trials, positive or negative, regarding efficacy of volatile anesthetic neuroprotection. There is little evidence that use of these drugs during an ischemic insult isadverse. Therefore, it remains premature to state that use of volatile anesthetics in the perioperative environmentwill provide sufficient protection to allow the brain to have increased tolerance to an ischemic insult. At the sametime, if an anesthetic is required, moderate doses of volatile anesthetics can be considered.
Nitrous Oxide
Nitrous oxide increases cerebral metabolic rate and it has been suggested that this serves to worsenischemic outcome. Early studies supported this work,
33
but modern studies with thermoregulated animals and long-term outcome analysis have failed to identify adverse effects of nitrous oxide.
34
There are no clinical trials that haveaddressed this issue. One must question the value of nitrous oxide in a resuscitation environment in which provision
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