Longitudinal evaluation of neurobehavioral outcomes after carotid revascularization.

BACKGROUND: Carotid revascularization, including carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS), is performed for stroke risk reduction but may also impact cognitive function. Cognitive outcomes observed after carotid revascularization have been inconsistent, and mechanistic relationships with procedural factors are poorly understood. To further explore associations between carotid revascularization and cognitive outcomes, a prospective longitudinal evaluation was conducted of patients undergoing elective CEA or CAS for hemodynamically significant carotid stenosis. METHODS: Patients undergoing primary carotid artery revascularization for hemodynamically significant stenosis were evaluated with neurologic and neuropsychological testing at baseline and at 1 and 6 months after revascularization. A subgroup of patients was also studied with baseline and postoperative magnetic resonance imaging (MRI). Outcomes included neurologic or neuropsychological deficits and imaging findings (including quantitative assessment of cerebral blood flow). RESULTS: Sixteen patients underwent carotid revascularization with both preoperative and postoperative neurologic and neuropsychological testing; preoperative and postoperative MRIs were also performed on eight patients. Five of 16 treated carotid lesions (31%) were considered symptomatic, and severity of carotid stenosis was 60-79% for 6 of 16 lesions and 80% or more in all others. A single perioperative neurologic deficit was identified; all other patients (15/16) had no abnormalities detected by neurologic examination. Neuropsychological testing identified new postoperative deficits in 3 patients (19%), among whom 2 had a normal neurologic examination at all time points, whereas 1 had clinical evidence of stroke. Quantitative analysis of mean cerebral blood flow revealed postrevascularization increases for both gray matter (48.6 ± 13.9 mL per 100 g/min vs 75.3 ± 70.8 mL per 100 g/min) and white matter (31.8 ± 10.6 mL per 100 g/min vs 55.2 ± 30.1 mL per 100 g/min)(P = 0.04). New postoperative MRI foci of restricted diffusion were identified in 2 patients, both of whom had no neurologic or neuropsychological deficit. Among patients with postoperative neuropsychological deficits, MRI revealed globally increased cerebral perfusion without new postoperative abnormalities in 2 of 3. CONCLUSIONS: The relationship between carotid revascularization and cognitive function is complex, and cognitive deficits may occur in the presence of increased cerebral perfusion without detectable embolization.

Cannula design reduces particulate and gaseous emboli during cardiopulmonary bypass for coronary revascularization.

PURPOSE: The incidence of neurocognitive deficits after coronary bypass surgery remains problematic, with atheroembolism being one of the major causes. External manipulation of aorta and the "sandblasting" effect of the high-velocity perfusion jet can cause dislodgement of atheromatous debris. DESCRIPTION: A new arterial cannula features a tip configuration that diffuses the flow through multiple outlets, providing reduced velocity and shear with one central and three diverted flow streams. EVALUATION: Between March 2007 and July 2008 twenty patients having isolated coronary artery bypass operations were instrumented with an Embolus Detection and Classification transducer. These data were compared to 43 patients from a previous study using similar techniques except for a standard open-tip arterial cannula. Total embolic counts were markedly lower in the new cannula group (20±25 vs 174±378) as were both gaseous (11±15 vs 95±211) and particulate counts (9±11 vs 80±194). CONCLUSIONS: The select 3D cannula design reduces the sandblasting effect of the perfusion jet and, also, may direct emboli from the heart and cardiopulmonary bypass equipment away from the cerebral circulation.

Consensus statement: minimal criteria for reporting the systemic inflammatory response to cardiopulmonary bypass.

The lack of established cause and effect between putative mediators of inflammation and adverse clinical outcomes has been responsible for many failed anti-inflammatory interventions in cardiopulmonary bypass (CPB). Candidate interventions that impress in preclinical trials by suppressing a given inflammation marker might fail at the clinical trial stage because the marker of interest is not linked causally to an adverse outcome. Alternatively, there exist examples in which pharmaceutical agents or other interventions improve clinical outcomes but for which we are uncertain of any antiinflammatory mechanism. The Outcomes consensus panel made 3 recommendations in 2009 for the conduct of clinical trials focused on the systemic inflammatory response. This panel was tasked with updating, as well as simplifying, a previous consensus statement. The present recommendations for investigators are the following: (1) Measure at least 1 inflammation marker, defined in broad terms; (2) measure at least 1clinical end point, drawn from a list of practical yet clinically meaningful end points suggested by the consensus panel; and(3) report a core set of CPB and perfusion criteria that maybe linked to outcomes. Our collective belief is that adhering to these simple consensus recommendations will help define the influence of CPB practice on the systemic inflammatory response, advance our understanding of causal inflammatory mechanisms, and standardize the reporting of research findings in the peer-reviewed literature.

Statistical significance versus clinical significance.

Unfortunately, the data were statistically nonsignificant due to insufficient power and poor experimental design. Conversely, many large clinical trials obtain a high level of statistical significance with miniscule differences between groups, which are completely clinically irrelevant. However, with proper marketing, billions can be made from results of dubious clinical importance. In this article, the differences between statistical and clinical significance are briefly discussed.

Consensus statement: Defining minimal criteria for reporting the systemic inflammatory response to cardiopulmonary bypass.

The causal factors of the systemic inflammatory response to cardiopulmonary bypass (CPB) were correctly identified in the early 1990 s: "... activation of complement, coagulation, fibrinolytic, and kallikrein cascades, activation of neutrophils with degranulation and protease enzyme release, oxygen radical production, and the synthesis of various cytokines from mononuclear cells" [Butler 1993]. Why therefore have clinical advances to curb the systemic inflammatory response proven such a disappointment? Part of the problem is that cardiac surgery has never taken intellectual ownership of this issue, borrowing its diagnosis from critical care medicine and failing to define the minimal criteria that should be measured when reporting on the systemic inflammatory response. An evidence based review of the current literature by many of the coauthors on this paper found that the majority of studies on the systemic inflammatory response did not measure a single one of the causal factors listed above - thus hindering our ability to identify mechanisms of causation and identify drug targets [Landis 2008]. A panel of experts convened at the Outcomes XII meeting, Barbados 2008, drafted the present consensus document in order to provide a framework to guide future studies and interdictions of the systemic inflammatory response. Herein, we have recommended: 1) mandatory reporting of minimal CPB and perfusion criteria that may affect outcomes, 2) reporting of a minimal set of causal inflammatory markers linked to adverse sequelae, and 3) reporting of at least one clinical end-point of organ injury, from a list of endpoints and markers of organ injury that balance practicality with clinical meaningfulness. It is our collective belief that this document will serve as a foundation for furthering our understanding of the influence of CPB practice with the systemic inflammatory response by standardizing the reporting of research findings in the peer-reviewed literature.

Cannulae and cell saver design: do they make a difference?

In the evolution of cardiopulmonary bypass (CPB), it is becoming increasing obvious that minimizing microembolization is critical in protecting the brain. Every component of the CPB circuit and ancillary apparatus must be evaluated and, if necessary, re-engineered with the reduction of microemboli a major focus. Cardiotomy suction has been identified as a major source of lipid microemboli. However, is the alternative blood treatment apparatus, the cell saver, capable of reducing the lipid embolic load and are all cell savers equally efficient? In the event that microemboli do make it to the aorta, is it possible to divert them away from the brain to more robust vascular beds through clever design of the aortic cannula? Is the venous cannula a source of microgaseous emboli? The answer is yes to both questions. Emboli can be directed away from the brain by the positioning and design of the aortic cannula and the venous cannulae may be a source of gaseous microemboli delivered to the oxygenator by the venous line but careful practice will prevent this type of embolic formation.

Deformable emboli and inflammation: temporary or permanent damage?

Neurologic sequelae after cardiopulmonary bypass have a multi-factorial etiology. Although it is typically thought that a neurologic dysfunction means a focal lesion, symptoms of a brain disorder can be initiated by metabolic disruption such as from hyper- or hypoglycemia, hypercalcemia, renal and hepatic injury, fatigue, and anesthesia. However, one of the most important causes of acute neurologic dysfunction is edema. Brain swelling is associated with the systemic inflammatory response and the passage of deformable microemboli. The larger question is whether acute symptoms associated with brain swelling because of a breakdown of the blood-brain barrier contributes to a long-term negative outcome caused by cell loss.

Twenty years trying to protect the brain: what do we know?

Thirty-five years ago at the Nixon Watergate hearings, a young attorney named Fred Thompson, current US presidential candidate, asked "What did the President know and when did he know it?" A couple of word changes and this question would be appropriate to ask any number of surgical specialties regarding negative neurologic outcomes. Even today, some specialties are in denial about impaired brain function after surgical intervention. Fortunately, the cardiac surgery community has been in the forefront in efforts to protect the brain.

Embolic factors associated with cardiac surgery.

Macro and microemboli can both cause significant neurologic dysfunction. The traditional belief in cardiac surgery was that the damage perpetrated by an embolus was caused by the occlusion of an arterial branch, resulting in an ischemic event and subsequent infarction. However, ongoing research has demonstrated that the mere passage of a deformable embolus (air, lipid, or semi-solid clot) will disrupt the endothelium as it is extruded through the vessel. A cascade of events follows endothelial irritation. In the closed environment of the brain, a disruption of the blood-brain barrier has been demonstrated after the passage of lipid microemboli. A significant breakdown of the blood-brain barrier causes marked brain swelling, increased intracranial hypertension, and a possible increase in the size of the lesions associated with larger occlusive emboli. Gaseous microemboli are also a well-documented endothelial irritant and can cause significant brain dysfunction. It is important to avoid delivering emboli of any size or composition to the cerebral vasculature in order to reduce the impact of cardiac surgery on the brain.

Does vacuum-assisted venous drainage increase gaseous microemboli during cardiopulmonary bypass?

BACKGROUND: Vacuum-assisted venous drainage enables adequate drainage through small-diameter cannulas but concerns are that it results in more gaseous microemboli delivered to the patient. METHODS: Five identical embolus detectors monitored the propagation of entrained air through a cardiopulmonary bypass (CPB) model. The ability of the CPB circuit to remove gaseous microemboli was studied with vacuum-assisted venous drainage and gravity siphon venous drainage using different pump speeds and rates of gaseous microemboli delivery. RESULTS: Under all conditions entrained venous air resulted in the detection of gaseous microemboli in the perfusate after the arterial filter. In blood-primed circuits, increased flow rates and higher levels of vacuum-assisted venous drainage were independently associated with increased gaseous microemboli counts in the arterial line. Vacuum-assisted venous drainage at -40 mm Hg did not significantly increase gaseous microemboli activity when compared with gravity siphon venous drainage at 4 L/min flow rate. CONCLUSIONS: Vacuum-assisted venous drainage at -40 mm Hg does not statistically reduce the ability of the CPB circuit to remove gaseous microemboli at lower pump rates. High levels of vacuum and increased pump flow rates should be avoided. Air should not be introduced into the venous line.

Emboli and Neuropsychological Outcome Following Cardiopulmonary Bypass.

The dramatic decline in mortality related to cardiac surgery has resulted in over 330,000 surgeries involving cardiopulmonary bypass (CPB) being performed yearly in the United States. Although few patients die as a result of cardiac surgery, over two thirds of the patients demonstrate evidence of acute neuropsychological dysfunction postoperatively. The potential mechanisms contributing to post-CPB neuropsychological deficits are many, but two major inter-related etiologic factors, hypo-perfusion and emboli, are suggested as the probable culprits. If embolism is the cause of the deficits, increasing cerebral perfusion would deliver more emboli and increase the amount and severity of injury. Conversely, if hypoperfusion is the cause of the injury, then decreasing brain blood flow to minimize embolic delivery would increase the likelihood of perfusion injury. By monitoring the carotid arteries of patients undergoing coronary artery bypass graft surgery, we have determined the frequency and quantity of embolic signals that occur during CPB. Although we have not been able to determine the nature of the embolus, gaseous or solid, we have demonstrated a relationship between the overall embolic load and the probability of having NP dysfunction. (ECHOCARDIOGRAPHY, Volume 13, September 1996)

Histologic Studies of Brain Microemboli in Humans and Dogs After Cardiopulmonary Bypass.

Emboli become lodged in the brains of patients undergoing cardiopulmonary bypass (CPB) and can cause death, stroke, or more subtle neurological and neuropsychological deficits. Using a specialized vascular stain (for alkaline phosphatase) in autopsy tissues from the brains of patients who underwent CPB shortly before death, we found large numbers of microemboli. All of these microemboli contain lipid, some contain small birefringent particles, and some may contain aluminum or silicon. Within a few weeks after CPB, most of the microemboli had disappeared from the brain tissues, but some persisted for at least 6 months. After several days, the endothelial cells of some of the vessels containing microemboli showed subtle damage in the form of loss of alkaline phosphatase reactivity, and some vessels appeared to be degenerating. Sometimes the surrounding neuropil also showed degeneration. Since skin and muscle biopsies can be readily obtained before, during, and after CPB, we investigated their suitability as surrogate tissues for brain; however, they were unsuitable because they had so few microemboli. By injecting microspheres into dogs at various times during CPB, we have investigated the timing of the production of microemboli. We are also exploring the use of rat brains to trap microemboli from the injected blood of patients undergoing CPB. (ECHOCARDIOGRAPHY, Volume 13, September 1996)

Noncardiac surgery brain injury: etiologic factors and prevention.

EXCERPT: During total joint arthroplasty, showers of bony spicules, marrow fat, and clot are carried by venous blood to the lungs, creating conditions not unlike those present in patients who have suffered traumatic long bone fractures. There is recent evidence that, like the fat embolism syndrome (FES), which often has a component of neurologic dysfunction, total joint arthroplasty and femoral nailing are associated with intraoperative brain embolization as determined by transcranial Doppler ultrasonography, and magnetic resonance brain imaging. Although there are good data demonstrating that intraoperative brain embolization occurs during total joint arthroplasties, the makeup and, even more importantly, the clinical significance of these emboli remain speculative. Brain microemboli resulting from cardiac surgery occur by the millions and may cause focal ischemia resulting in significant neurologic dysfunction. Our studies suggest that the major source of these microemboli is lipid droplets of the patient's fat that drip into the blood in the surgical field. This lipid-laden blood is aspirated and then returned to the patient via the cardiopulmonary bypass (CPB) apparatus. Our investigations have focused on the causes (microemboli), consequences (brain damage), and strategies for elimination of brain lipid microemboli resulting from salvaged blood collected during surgery.

How effective are cardiopulmonary bypass circuits at removing gaseous microemboli?

An association has been demonstrated between intravascular microemboli and organ injury during cardiopulmonary bypass (CPB). Air may be inadvertently introduced into the venous line during CPB resulting in the formation of gaseous microemboli (GME). We studied the ability of CPB circuits, from five different manufacturers, to remove GME originating from the introduction of air into the venous line. Using an in vitro model of adult CPB, 60 ml of air was introduced into the venous line and the progression of GME through the circuit components was monitored at 5 locations. In all circuits GME were detected in the arterial line following the introduction of air into the venous line. There was a wide variation between manufacturers in the ability of the circuit to remove GME. Air introduced into the venous line during CPB results in the formation of GME that are able to pass through all the circuit components including the arterial filter. The quantity of GME detected in the arterial line is influenced by the design of the circuit components and varies between manufacturers. Air in the venous line should be avoided and if present it must be dealt with promptly.

Coronary artery bypass grafting with single cross-clamp results in fewer persistent neuropsychological deficits than multiple clamp or off-pump coronary artery bypass grafting.

BACKGROUND: In coronary artery bypass grafting (CABG) patients, neuropsychological deficits that are present from the time of the operation through 6 months postoperatively are considered permanent and represent organic brain damage related to the operation. We hypothesized that changes in our surgical method would reduce persistent deficits. METHODS: From 1999 to 2004, consenting CABG patients were randomly assigned to multiple aortic cross-clamp or single aortic cross-clamp technique. An additional contemporary group of patients treated with off-pump CABG was studied. All patients underwent an 11-part neuropsychologic examination preoperatively, and at 1 week, 6 weeks, and 6 months postoperatively. One hundred seven patients with no postoperative neurologic deficits had neuropsychologic examinations at all four testing periods. RESULTS: Off-pump CABG patients were significantly younger (60 +/- 11 years) than multiple aortic cross-clamp (66 +/- 8 years) and single aortic cross-clamp (64 +/- 9 years; p < 0.05) patients. At 6 months, 26% of 27 multiple aortic cross-clamp patients had neuropsychological deficits, 27% of 26 off-pump CABG patients had neuropsychological deficits, and only 9% of 54 single aortic cross-clamp patients had neuropsychological deficits (p = 0.067 versus multiple aortic cross-clamp and off-pump CABG). CONCLUSIONS: These results suggest that surgical technique is very important in determining cognitive outcome after CABG. Cardiopulmonary bypass is not the most important factor in determining outcome and when carefully performed with single cross-clamp and minimal aortic manipulation is equal or may be superior to off-pump operation. We suspect that mild hypothermia in on-pump surgery is additionally neuroprotective, a factor that should be taken into account when planning an operation.

Preliminary report: functional MRI of the brain may be the ideal tool for evaluating neuropsychologic and sleep complaints of patients with primary hyperparathyroidism.

BACKGROUND: The incidence, pattern, and severity of sleep disturbance and cognitive dysfunction has not been well characterized for patients with primary hyperparathyroidism (PHPT). There is no agreement on the mechanism of the development or resolution of such symptoms, and in no previous study has cerebral activity been functionally assessed and change documented following surgical cure of patients with PHPT. METHODS: We undertook a prospective analysis to obtain pilot data on 6 patients with PHPT. Functional magnetic resonance imaging (fMRI), formal neuropsychologic (NP) tests, and health-related quality of life (HRQL) measures that included sleep assessments were performed on patients before and after parathyroidectomy. Changes in cortical activation under both conflict and neutral conditions (distracting tasks) were recorded. RESULTS: Functional MRI demonstrated postoperative changes in medial prefrontal cortex activity during cognitive processing of conflict and nonconflict tasks. Further postoperative changes were noted in the dorsolateral prefrontal cortex and parietal cortex with shifts in activations. In addition to the fMRI findings, the patients demonstrated improvements in sleep and social behavior. They tended to experience less fatigue and their processing speed on cognitive tests improved. CONCLUSIONS: These data support the feasibility and willingness of patients with PHPT to undergo fMRI assessment. Preliminary findings reflected a generalized improvement in processing efficiency postoperatively compared with a patient's preoperative state, and the HRQL measures showed improved sleep. These findings mirror those expected with sleep dysfunction. Longitudinal assessment with advanced brain imaging technology, neuropsychological (NP), and sleep evaluations is warranted to further explore cognitive, sleep, and HRQL improvement after parathyroidectomy.

Single crossclamp improves 6-month cognitive outcome in high-risk coronary bypass patients: the effect of reduced aortic manipulation.

OBJECTIVE: We hypothesized that a strategy that reduced aortic manipulation would reduce the incidence of cognitive deficits in patients undergoing coronary artery bypass grafting compared with the "traditional" approach and that neurobehavioral outcomes with the reduced aortic manipulation strategy would approach those obtained with off-pump coronary artery bypass surgery. METHODS: Consenting high-risk patients (those with older age, diabetes, or hypertension) scheduled for coronary artery bypass grafting and cardiopulmonary bypass were randomly assigned to 1 of 2 aortic management protocols: (1) a traditional approach in which distal anastomoses were accomplished while the aorta was crossclamped but in which proximal anastomoses were sewn while a partial occlusion clamp was applied to the aorta (multiple aortic clamping group) or (2) a reduced aortic manipulation approach in which the aorta was clamped a single time with a reduced-pressure clamp (single aortic clamping group) and the partial occlusion clamp was not used. A contemporaneous group of patients undergoing off-pump coronary artery bypass surgery without cardiopulmonary bypass was also enrolled. Subjects in all 3 groups underwent neurologic and neuropsychological testing before and after surgery. After randomization, patients assigned to either approach could be changed to another strategy if the attending surgeon determined that patient safety demanded this change. The study design anticipated that surgical techniques would evolve over the course of patient enrollment and anticipated that some patients would have intraoperative echocardiographic findings that would demand that the traditional approach (eg, severe aortic atherosclerosis) or the reduced manipulation protocol (eg, severe ischemia or poor left ventricular function) be abandoned. Thus, an unequal distribution of patients was expected. By surgeon decision, 20 of 84 multiple aortic clamping patients crossed over to single aortic clamping, and 3 of 85 single aortic clamping patients switched to multiple aortic clamping. Eligible patients had a battery of neuropsychological tests before surgery and at 6 months after surgery. A 20% decrement in 2 or more tests was defined as a neuropsychological deficit. RESULTS: [table: see text]. CONCLUSIONS: A surgical strategy designed to minimize aortic manipulation can significantly reduce the incidence of cognitive deficits in coronary artery bypass grafting patients compared with traditional techniques. In this series, the results of the reduced aortic manipulation strategy were not significantly different from those in patients having off-pump coronary artery bypass surgery, thus emphasizing surgical technique as the primary cause of brain damage in coronary artery bypass grafting patients.