Curr Treat Options Neurol (2015) 17:28 DOI 10.1007/s11940-015-0357-2

Critical Care Neurology (K Sheth, Section Editor)

Neuroprotection After Major Cardiovascular Surgery Jose Torres, MD* Koto Ishida, MD Address * Department of Neurology, NYU Langone Medical Center, 530 First Avenue, Suite 5A, New York, NY 10016, USA Email: [email protected]

* Springer Science+Business Media New York 2015

This article is part of the Topical Collection on Critical Care Neurology Keywords Neuroprotection I Lidocaine I Hypothermia I Magnesium sulfate I Dexmedetomidine I Erythropoietin I Cardiovascular I Surgery

Opinion statement Neurologic injury is a common complication of major cardiovascular procedures including coronary artery bypass graft (CABG) surgery, coronary valve replacement, and aortic aneurysm surgery. However, despite ongoing research in the field of neuroprotection, there are currently few pharmacologic and interventional options to effectively protect the brain and spinal cord in the postoperative period. CSF drainage after aortic surgery currently stands as the only neuroprotective intervention that has been consistently shown to protect the spinal cord from ischemic injury, leading to significantly fewer patients with paraplegia and paraparesis. There is promising but conflicting evidence about the potential benefits of agents such as dexmedetomidine, lidocaine, magnesium, and erythropoietin in preventing postoperative stroke and cognitive dysfunction. Postoperative hypothermia has also been studied in preventing neurologic injury after cardiopulmonary bypass. With the rate of cardiovascular surgeries increasing yearly, further investigations are needed to validate many of these therapies and discover new ways to protect the brain and spinal cord from intraoperative and postoperative injuries in this high-risk population.

Introduction Neurologic injury is a common complication of major cardiovascular surgery as a result of thromboembolism, inflammation, and hypoperfusion [1•, 2•]. Postoperative magnetic resonance imaging studies have demonstrated new ischemic lesions in up to 27.6 % of patients after coronary artery bypass graft (CABG) surgery, 63 % after aortic surgery, and 84 % after valve replacement [3–

7]. However, a large proportion of patients do not develop focal neurologic symptoms after surgery and instead are noted to have significant cognitive dysfunction, indicating that thromboembolism is not the sole cause of the injury sustained and, likely, acts synergistically with inflammation and hypoperfusion to cause neurologic injury. This cognitive dysfunction, usually defined

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as scoring 0.5 to 1 standard deviation below preoperative norms, has been reported to be as high as 53 % at discharge and 42 % 5 years after CABG [2•]. Similar rates have been reported in patients undergoing valve replacements with patients who undergo concurrent valve replacement and CABG experiencing the highest rates of postoperative neurologic dysfunction [8]. Cognitive decline and postoperative delirium have also been reported in patients that undergo aortic aneurysm repairs with rates ranging from 15 to 33 % [9–11]. However, the most feared complication of aortic surgery has been spinal cord ischemia with subsequent paraparesis or paraplegia as a result of intraoperative interruption of blood flow to the spinal cord, inadequate revascularization of spinal arteries during aortic reconstruction, postoperative spinal artery vasospasm, or increased spinal fluid pressure [12•]. While less frequent than cerebral ischemia and cognitive decline, prevalence has been reported to be between 6 and 40 %, with lower

rates seen in patients that undergo endovascular surgery [12•, 13]. Because these neurologic complications lead to increased hospital and ICU lengths of stay as well as significant postsurgical morbidity and mortality [2•, 14, 15], much research has focused on ways to reduce the deleterious effects of inflammation, hypoperfusion, and thromboembolism. The holy grail of this research has been the development of pharmacologic and interventional options that decrease postoperative fluctuations in blood pressure, reduce transmembrane ion shifts that can result from administration of large quantities of intravenous fluids, block inflammatory/ oxidative pathways that lead to neuronal death, and prevent the release of excitotoxic neurotransmitters— all of which cause significant neuronal injury. Below is a review of studied treatments that have shown promising efficacy in improving neurologic outcomes after major cardiovascular procedures.

Treatment Pharmacologic treatment Dexmedetomidine Dexmedetomidine is a highly selective alpha-2 adrenoreceptor agonist with sedative, anxiolytic, and analgesic properties. Its sedative properties result from stimulation of adrenoreceptors in the locus coeruleus, and because there is no activation of GABA receptors, it results in significant sedation without respiratory suppression. Additionally, it decreases sympathetic transmission from the brain to the periphery, reducing circulating catecholamines and, therefore, the potential for large fluctuations in blood pressure. Finally, dexmedetomidine inhibits nociceptive transmission via its actions on adrenoreceptors in the dorsal horns, reducing patients’ need for pain medications postoperatively [16]. The use of dexmedetomidine in the postoperative period has been demonstrated to reduce the incidence of postsurgical delirium. Maldonado et al. studied the effects of postoperative sedation on 118 patients who underwent valvular surgery. In this open-label, prospective, randomized trial, 40 patients received dexmedetomidine, 38 received propofol, and 40 received midazolam in the first 24 h after surgery. The dexmedetomidine group received a 0.4 μg/kg bolus followed by an infusion of 0.2 to 0.7 μg/kg/h. They were screened for delirium daily for 3 days after surgery. Delirium was confirmed by a neuropsychologist per DSM-IV criteria. The authors found a 3 % incidence of delirium in the dexmedetomidine group, 50 % in the propofol group, and 50 % in the midazolam group (pG0.001). Those that developed delirium had longer ICU and in-hospital stays, leading to higher costs of care (pG0.001) [17•].

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In a retrospective cohort study of patients that underwent CABG, valvular surgery, or a combination of both, Ji et al. examined 1134 patients, 568 of which received dexmedetomidine 0.24 to 0.6 μ/kg/h during surgery and in the first 24 h postoperatively. They looked at in-hospital, 30-day, and 1-year mortality as well as the in-hospital incidence of transient ischemic attacks, stroke, coma, and delirium, defined as confusion, illusions, or Bcerebral excitement.^ They found that dexmedetomidine not only was safe but also led to significant reductions in in-hospital (1.23 vs. 4.59 %, pG0.0001) and 30-day mortality (1.76 vs. 5.12 %, pG0.0001) as well as postsurgical delirium (5.46 vs. 7.42 %, p=0.003). However, they did not demonstrate any significant difference in the incidence of stroke (1.41 vs. 1.06 %, p=0.76) or coma (0.35 vs. 0.53 %, p=0.23) [18]. Although both studies demonstrated benefit in preventing delirium, there were some important differences. In the Ji study, primary and secondary outcomes were measured until discharge even if length of stay was more than 30 days while the Maldonado study only assessed patients in the immediate postoperative period. This not only allowed for a larger window during which neurologic outcomes could be detected but also included periods where factors other than the sedation used (i.e., infection, medications, etc.) were more likely to contribute to neurologic dysfunction, therefore, blunting the measurable differences between the treatment groups. Also, although the Ji study was large, it was not a randomized controlled trial resulting in significant baseline differences in the treatment groups. Higher incidences of congestive heart failure, low ejection fraction, renal failure, and dyslipidemia were noted in the dexmedetomidine group which may have increased risk of stroke and neurologic injury, contributing to the nonsignificant result. Thus, while dexmedetomidine appears to reduce postoperative delirium, its role in prevention of other forms of neurologic injury and cognitive decline has not been well studied, and further randomized controlled trials are needed to better assess this. Nevertheless, it appears to be a promising intervention in the immediate postoperative period and may be considered in post-CABG and valve surgery patients who are at elevated risk for delirium.

Erythropoietin Neurons and astrocytes have been shown to express erythropoietin receptors in response to hypoxia, making erythropoietin a potential pharmacologic target for neuroprotection. Animal models have demonstrated that when erythropoietin binds these receptors, it promotes antiapoptotic, anti-inflammatory, and antioxidant pathways that protect neurons from ischemia [19, 20, 21••]. Given these preclinical data, erythropoietin has been studied in the acute stroke period as a way to protect penumbral tissue. Ehrenreich et al. demonstrated its potential neuroprotective properties in a safety and proof of concept doubleblind, randomized controlled study of 53 patients in 2002. Patients received 3.3×104 IU of erythropoietin for three consecutive days after stroke (total dose 100,000 IU). Both adverse events and severe functional disability (modified Rankin scale (mRS) ≥5 or Barthel index (BI) G20) were evaluated. At 1 month, only 14 % in the erythropoietin group had severe disability by mRS criteria vs. 37 % in the placebo group (p=0.07) and 14 vs. 42 % by BI criteria (pG0.05). There were no reported severe adverse events [22].

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Curr Treat Options Neurol (2015) 17:28 Given these encouraging findings, Haljan et al. examined the effects of erythropoietin on cognition in a randomized controlled trial of 32 patients who underwent CABG. Patients received either 0, 375, 750, or 1500 U/kg, starting on the day of surgery and continuing for 3 days. Extensive neurocognitive testing including the Folstein mini-mental test, the Beck anxiety and depression scales, and full neurological examinations were obtained preoperatively (within 1 month before surgery), on the day of discharge, and at the 2-month follow-up. Cognitive decline was defined as a 20 % reduction in performance from preoperative baseline in 20 % of the tests. At 2 months, there was a trend toward improved cognitive function in the treatment group with neurocognitive deficits occurring in 38 % of patients that did not receive erythropoietin and 8.3 % of patients that did (p=0.085) [23]. In another small prospective trial, Lakic et al. examined 20 patients undergoing CABG. Ten patients received erythropoietin 24,000 IU on the day of surgery and again 24 and 48 h after surgery. MRIs and neurological examinations were performed within the first 5 days after surgery to evaluate for focal neurologic changes and ischemia. They found that 4 of 10 patients in the placebo group had clinically significant strokes while no patients in the erythropoietin group had clinically significant neurologic events [24]. While these small trials demonstrated the potential neuroprotective effects of erythropoietin in postoperative CABG patients, more recent data has called its overall safety into question. In a 2009 double-blind, placebo-controlled randomized study of 522 patients with MCA territory infarcts and a National Institutes of Health Stroke Scale (NIHSS) ≥5, 238 patients received 40,000 IU of erythropoietin within 6 h of stroke onset and again at 24 and 48 h. NIHSS, mRS, and Barthel index were assessed at enrollment, 24 and 48 h; and 7, 30, and 90 days by blinded raters. No statistically significant difference was seen in these neurologic outcome measures at 90 days. More importantly, despite similar baseline characteristics, mortality in the erythropoietin group was 16.4 % compared with 9 % in the placebo group (p=0.001), highest in the first week of stroke (47.6 %) due to increased incidence of intracerebral hemorrhage (27.5 %), brain edema (14.2 %), and thromboembolism (14.2 %). Subgroup analyses indicated a significantly higher mortality rate in patients that were treated with both intravenous tissue plasminogen activator (IV-tPA) and erythropoietin compared to those not getting IV-tPA, raising the possibility of an IV-tPA-erythropoietin interaction. However, those that died had a higher baseline NIHSS before receiving study drug (20.4±5.4 vs. 13.3±4.9) and the death rate in the erythropoietin group was comparable to death rates in patients with similar stroke severity in prior stroke trials while the mortality rate in the placebo group was unexpectedly lower than prior trials, indicating that perhaps the increased mortality in the treatment group may have been due to the pretreatment severity of the stroke instead of the treatment itself [21••]. These data demonstrate that while erythropoietin appears to have some neuroprotective properties, further research is needed to determine the conditions under which it should be used. The Ehrenreich study raises questions about its use in post-IV-tPA patients and those with high baseline NIHSS who may be at higher risk of developing cerebral edema, intracerebral hemorrhage, and thromboembolic events from immobilization. Many of these concerns may be less applicable to the postsurgical population who may not have

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ischemic lesions at all, let alone large volume infarcts. Additionally, these postoperative patients are generally not candidates for IV-tPA. Nevertheless, the studies that demonstrated efficacy in postsurgical patients were very small, and further research will be needed to confirm safety and efficacy in this population.

Lidocaine Animal models have shown that lidocaine protects neurons during hypoxicischemic conditions by decreasing transmembrane ion shifts [25], cell metabolic rate [26], and excitotoxic neurotransmitter release [27]. These models have also suggested that lidocaine may lead to a smaller infarct size [28] and preservation of cerebral blood flow [29]. Similar potential has been seen in human trials. Mitchell et al. demonstrated the potential efficacy of lidocaine in a prospective study of 55 left heart-valve surgery patients in 1999. Twenty-eight patients received a 1 mg/kg bolus of lidocaine over 5 min, 240 mg over the first hour, 120 mg over the second hour, and then 60 mg/h thereafter for a total of 48 h. All patients underwent six cognitive performance tests with 11 cognitive domains and two Bcontrol^ inventories for depression and anxiety before surgery then again at 10 days, 6 weeks, and 6 months. Cognitive decline was defined as 1 standard deviation below preoperative norms. A significantly greater proportion of patients in the placebo group demonstrated worsened neuropsychological testing at the 10-day and 10-week reviews. Moreover, the lidocaine group exhibited significantly better cognition in 5 of 11 cognitive domains at 6 months (pG0.05), demonstrating a sustained effect [30]. In a 2009 randomized controlled trial using a similar dosing protocol, Mathew et al. studied 277 CABG patients, 114 of whom received lidocaine. They performed five cognitive tests on the day prior to surgery, then again at 6 weeks and 1 year. There was no statistically significant difference in serious adverse events between the two groups (12.3 % of lidocaine and 10.2 % of placebo subjects) (p=0.68). However, by 6 weeks, there was also no difference in the prevalence of neurocognitive deficits, reported as 45.5 % in the lidocaine group vs. 45.7 % in the placebo group (p=0.97). Higher doses of lidocaine (935 mg/kg) were associated with cognitive dysfunction in a dosedependent fashion, and diabetic patients were more likely to have worsened cognitive function when treated with lidocaine (p=0.004). Post hoc analyses limited to nondiabetic patients receiving lidocaine at doses G42.6 mg/kg demonstrated significant neurocognitive benefit (p=0.024). Moreover, when the entire cohort was analyzed at 1 year, cognitive dysfunction was found in 40 % of treated patients and 51.7 % in untreated patients (p=0.185), with a trend toward better performance on neurocognitive testing in the lidocaine group (p=0.082). Notably, a large number of patients were lost to follow-up in this trial, and only 58.5 % of patients underwent testing at 1 year [31•]. Given these data, there is a suggestion that lidocaine may improve overall cognitive function in postoperative patients. However, the Mathew study suggests that in diabetic patients, it may actually do more harm than good and that efficacy may be dose dependent. Therefore,

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Curr Treat Options Neurol (2015) 17:28 more data are needed to establish the best dosing regimen as well as which patient populations may benefit the most while minimizing potential for harm prior to routine clinical use.

Magnesium sulfate Hypoxia and ischemia induce glutamate release into the extracellular space which in turn activates N-methyl-D-aspartate (NMDA) receptors leading to large ion shifts across neuronal membranes. This leads to cellular metabolic instability and, ultimately, cell death. Magnesium sulfate is a noncompetitive NMDA antagonist with the potential to prevent and mitigate the activation of these harmful cellular pathways [32, 33]. Moreover, it has been widely used for decades with an excellent safety record in the setting of pregnancy [33–38]. The potential neuroprotective effects of magnesium sulfate have been investigated in the setting of acute ischemic stroke [33, 39•]. However, to date, magnesium has not been shown to have a significant impact on disability after stroke. This was most recently evaluated in the FASTMAG Trial, a randomized, double-blind, placebo-controlled trial of 1700 patients presenting within 2 h of stroke onset. A total of 857 patients received 4 g of magnesium sulfate infused over 15 min followed by 16 g infused over 24 h. The primary outcome was mRS at 3 months. The authors found no significant shift in the distribution of 3-month disability outcomes on the mRS (p=0.28). There was also no significant difference in the number of patients with minimal or no disability (p=0.87) or functional independence (p=0.87) between the treatment groups. Serious adverse events were not statistically different (p=0.67) [39•]. Despite the lack of efficacy in the setting of acute stroke, Bhudia et al. investigated the potential use of magnesium for neuroprotection in the postoperative period after CABG and valvular surgery. Out of 350 patients, 174 received 780 mg of magnesium sulfate intravenously over 15 min during anesthesia induction, followed by 3160 mg over 24 h. The plasma magnesium level was measured every 15 min during cardiopulmonary bypass and if it decreased to less than 3.6 mg/dL, additional doses were given to maintain levels between 3.6 and 4.8 mg /dL. There were no significant differences in adverse events between the two groups. One percent of patients in the magnesium group and 3 % in the placebo group experienced stroke (p=0.3). Patients underwent a battery of 14 neuropsychological tests evaluating mentation, motor function, coordination, and sensation preoperatively, 48, and 96 h after extubation. They also underwent other separate neuropsychological testing preoperatively and at 3 months. By 96 h, the patients in the magnesium group were more likely to return to preoperative performance levels compared with those in the placebo group (p=0.003). However, neuropsychological performance at 3 months was similar between the two groups (p=0.6). This result was likely impacted by the 59 patients that were lost to follow-up [40]. While there is insufficient data to recommend magnesium as an effective postoperative neuroprotectant, it is a safe medication with compelling,

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potentially neuroprotective biochemical properties. Further research will be needed to assess its role in the postoperative period.

Interventions Moderate hypothermia Hyperthermia has been associated with poor neurologic outcomes in the setting of ischemia by aggravating neuronal injury and accelerating neuronal death [41, 42]. Animal models, on the other hand, have shown that deliberate hypothermia can protect the brain from ischemic injury by lowering cellular metabolic rates and leading to a better balance between oxygen supply and demand [42, 43]. In fact, for each degree (measured in Celsius) brain temperature is decreased, the metabolic rate is reduced by 7 % [44]. Hypothermia also decreases release of excitotoxic neurotransmitters [45]; prevents blood-brain barrier dysfunction [46]; and reduces leukocyte adhesion to brain endothelium, preventing migration of potentially harmful inflammatory cells into the central nervous system [47]. Because of these findings, moderate hypothermia has been used for years during major cardiovascular surgery in an effort to protect at-risk neural tissue [48•]. However, after surgery, patients are rewarmed quickly and placement of arterial cannulas that inject warm fluid into the body in the neck can sometimes result in cerebral perfusion with hyperthermic fluids, potentially exacerbating intraoperative ischemic injury [1•]. In an effort to avoid this, Nathan et al. tested whether rewarming to 34 °C instead of the usual 37 °C immediately after surgery would confer a neuroprotective effect. Of 223 patients, 111 were rewarmed from 32 to 34 °C. Cognitive function was measured with a battery of eight neuropsychological tests spanning motor function, memory, and mood. Cognitive dysfunction, defined as a ≥0.5 standard deviation decrease in testing performance from preoperative norms in one or more cognitive domains, was reported in 48 % of hypothermic patients vs. 62 % of normothermic patients (p=0.048). The greatest benefit was seen in attention and speed. At 3 months, speed tasks were still faster in the hypothermia group by 3.1 s (p=0.003). Moreover, there were no statistically significant differences in adverse events [49]. Five years after surgery, those that did poorly in the first week postoperatively continued to demonstrate cognitive dysfunction. However, there was no significant difference between the two groups in terms of neurologic decline (defined by at least one standard deviation below initial score) [50]. Boodwani et al. looked at neurocognitive performance in patients treated with intraoperative and immediate postoperative hypothermia to 34 °C vs. normothermic temperatures (37 °C). As with the Nathan studies, patients underwent a diverse battery of neurocognitive tests and were deemed to have dysfunction if postoperative scores were 1 standard deviation below baseline scores. Among 267 patients at 3 months, 4 % in the hypothermia group (n=134) had cognitive decline vs. 8 % in the normothermia group (n=133). However, this difference did not reach statistical significance (p=0.28) [51]. While hypothermia appears to also have potential neuroprotective properties in the postoperative period, there are several potential drawbacks that hamper its use and may ultimately lead to decreased efficacy. Intubation, required for hypothermia protocols, independently increases patient morbidity.

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Curr Treat Options Neurol (2015) 17:28 Cooling can cause shivering, which can make temperature regulation difficult and increase oxygen consumption and metabolic demands. Hypothermia increases risk of infection by reducing the release of pro-inflammatory cytokines, inhibiting neutrophil and macrophage function. It reduces coagulation factor function and can lead to bleeding diatheses. Induction of hypothermia can cause large electrolyte shifts, which may in turn lead to cardiac arrhythmias. It can decrease sensitivity to insulin leading to hyperglycemia. Finally, hypothermia can cause large volume shifts either through hypothermia-induced diuresis or via vasodilation during rewarming [52]. These potential ion and fluid shifts may impact the efficacy of hypothermia and may have contributed to the nonsignificant results. Improved management of these complications and determination of optimal cooling temperature and rewarming method may ultimately lead to more significant and sustained cognitive benefits in postoperative patients.

CSF drainage Elective treatment of thoracic aortic aneurysms (TAA) and thoracoabdominal aortic aneurysms (TAAA) as well as emergent treatment of aortic aneurysmal rupture and aortic dissection carry significant risk of spinal cord injury. Incidence of paraparesis and paraplegia after elective operations of the infrarenal aortic arteries has been reported to be as low as 0.25 %. However, treatment of more extensive aortic disease, specifically extending from the proximal descending aorta to the infrarenal abdominal aorta, may result in neurologic injury in close to half of patients, with those requiring more emergent surgeries experiencing even higher complication rates. By some estimates, up to 21 % of these patients may end up paraplegic [53]. The cause of this injury is multifactorial, resulting from either inadequate revascularization after aortic surgery, spasm of the spinal microvasculature, or increased spinal fluid pressure. This increased pressure is thought to decrease blood flow to the spinal cord, therefore augmenting the first two mechanisms of injury. Because of this, CSF drainage has been explored as a neuroprotective intervention that aims to increase spinal blood flow and reduce the incidence of postoperative neurologic dysfunction [12•]. The first randomized study evaluating efficacy in humans in 1991 included 98 patients, 46 of whom underwent intraoperative drainage of CSF. A volume of 20 cc was removed immediately after catheter insertion followed by additional fluid removal to maintain CSF pressure between 10 and 15 mmHg with no more than 50 cc removed beyond what was lost during catheter insertion. Catheters were removed immediately postoperatively, and patients were evaluated for episodes of paraplegia or paraparesis during hospitalization and at 90day follow-up. There was no difference in outcome between the two treatment groups with 14 patients having paraplegia or paraparesis in the drainage group and 17 in the control group. However, at 90 days, there was a nonsignificant trend toward fewer paraplegic and more ambulatory patients in the drainage group [53]. This study was criticized for limiting the amount of CSF removal and for not continuing drainage postoperatively. In a 1998 study aimed at addressing these issues, Svennson et al. randomized 33 high-risk patients with extensive disease of the descending and/or abdominal aorta to either CSF drainage (n=17) or no drainage (n=16). The drain was placed before surgery, and 20 cc of CSF were

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removed immediately. During surgery and for a median of 40 h after the surgery, CSF pressure was kept between 7 and 10 mmHg. 11.8 % in the drainage group and 43.8 % of patients in the control group developed paraparesis or paraplegia (p=0.0392). The mean motor score was 3.88 in the treatment group vs. 3.25 in the control group (p=0.034), with 0 representing no movement and 4 normal movement. The only drainage-related complication was one patient with persistent CSF leak [54]. In a larger randomized controlled trial of 156 patients, 82 underwent CSF drainage. Catheters were placed preoperatively, and CSF was allowed to drain freely, maintaining CSF pressure under 10 mmHg. The drain was removed after 48 h in patients that had no deficit and continued for an additional time in those that developed neurologic deficits. Paraparesis or paraplegia occurred in 2.7 % of treated patients and 12.2 % of control patients (p=0.03). Catheters became occluded in two patients and dislodged in one patient. There were no other treatment-associated complications [55]. A 2012 meta-analysis included 13 studies examining rates of lower extremity deficits after thoracic and abdominal aortic surgeries. Of these, 10 studies showed efficacy of CSF drainage in reducing postoperative neurologic dysfunction (p=0.03). Those that did not show benefit reported Bnot infrequent^ incidence of CSF pressure over 15 mmHg and noted efficacy when CSF pressure was maintained consistently G10 mmHg. Infrequent catheter occlusion and dislodgement, headache, meningitis, and subdural hematoma were the most common adverse effects of CSF drainage [56•]. Similar efficacy was shown in a prior meta-analysis in 2004 by Cina et al. Data from 289 patients (150 treated, 139 controls) and five cohort studies totaling 854 patients (505 treated, 349 control) were included. The odds ratio for developing paraplegia in CSF drainage patients was 0.35 in randomized studies (p=0.5) and 0.26 in cohort studies (p=0.0002). They noted that out of 1396 patients, only three (0.2 %) experienced serious adverse events (two subdural hematomas requiring decompression and one fatal meningitis) [12•]. These data clearly demonstrate that CSF drainage after aortic surgery decreases postoperative rates of paraparesis and paraplegia. While complications including catheter occlusion or dislodgement, headache, meningitis, and subdural hematoma may occur, they tend to be infrequent and rarely clinically significant.

Conclusion The search for neuroprotective agents that can help the brain and spinal cord withstand diverse insults and minimize neurologic injury has been challenging. However, as this review demonstrates, there are several agents and interventions that have shown efficacy in achieving this goal and have led to improved patient outcomes. Thus far, it appears that only CSF drainage after aortic surgery can claim sufficiently robust data to be recommended for routine postoperative care. Although promising, insufficient or conflicting data regarding other neuroprotective options limit their clinical utility at present. Further research is

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needed to expand our armamentarium for preventing devastating neurologic injury in these high-risk postoperative patients.

Compliance with Ethics Guidelines Conflict of Interest Jose Torres and Koto Ishida declare no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the authors.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.•

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Neuroprotection after major cardiovascular surgery.

Neurologic injury is a common complication of major cardiovascular procedures including coronary artery bypass graft (CABG) surgery, coronary valve re...
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