Combined use of cerebral spinal fluid drainage and naloxone reduces the risk of paraplegia in thoracoabdominal aneurysm repair

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1 Combined use of cerebral spinal fluid drainage and naloxone reduces the risk of paraplegia in thoracoabdominal aneurysm repair c. w. Acher, MD, M. M. Wynn, MD, J. R. Hoch, MD, P. Popic, MD, Judy Archibald, RN, and W. D. Turnipseed, MD, Madison) Wis. Purpose: This report summarizes our experience with the use of cerebral spinal fluid drainage (CSFD) and naloxone for prevention of postoperative neurologic deficit (paraplegia or paraparesis). Methods: We reviewed 110 consecutive patients with 86 thoracoabdominal aneurysms and 24 thoracic aneurysms. The status of 47 patients (43%) was acute (rupture or dissection), and the status of 52 (47%) was Crawford type I or II. None of the patients had intercostal artery reimplantation. There were two patient groups for analysis of neurologic deficit risk. Group A (61 patients) received naloxone and CSFD, and group B (49 patients) did not. Results: One deficit occurred in group A and 11 deficits occurred in group B (p = 0.001). By multiple logistic regression analysis, the variables acute status, Crawford type II, or group B classification were significant factors for deficit risk. Use of the same logistic regression analysis on the subgroup of 47 patients with acute aneurysms and 33 patients with Crawford type 2 aneurysms confirmed the protective effect of combined CSFD and naloxone (group A) and that clinical presentation and extent of aorta replaced are the primary risk factors for development of deficit. To test this conclusion we developed a highly predictive model (correlation coefficient with 16 series of thoracoabdominal aneurysms) for neurologic deficit. We applied our data to this model. Group B had the predicted number of deficits, and group A had substantially fewer deficits than predicted. Conclusions: We conclude that the combined use of CSFD and naloxone offers significant protection from neurologic deficits in patients undergoing thoracoabdominal and thoracic aortic replacement. (J VAse SURG 1994;19: ) The risk of spinal cord ischemia and neurologic deficit (paraplegia and paraparesis) during thoracic aortic surgery is the same today as it was in 1956 when Adams and Van Geertruyden 1 presented their comprehensive analysis of the subject. Their words are as relevant today as they were 37 years ago: "It is amazing to consider how few difficulties were encountered by interrupting the (thoracic) circulation... The spinal cord, however, is the one organ on which the effects of vascular occlusion remain unsolved... In fact when these accidents (paralysis) From the University of Wisconsin Hospital, Madison. Presented at the Forty-seventh Annual Meeting of the Society of Vascular Surgery, Washington, D.C., June 8-9, Reprint requests: C. W. Acher, MD, 600 Highland Ave., H4/730B, Madison, WI Copyright 1994 by The Society for Vascular Surgery and International Society for Cardiovascular Surgery, North American Chapter /94/$ /6/ occur, the operative conditions are identical to those in many similar but successful cases." Since Adams and Van Geertruyden 1 described the anatomic and pathophysiologic mechanism of spinal cord infarction from interruption of thoracic aortic blood flow, scientists and physicians have accumulated a wealth of information on factors that affect spinal cord ischemia associated with thoracic aortic surgery. However, even today, "understanding is difficult because of both the interaction of so many structural and dynamic variables in the circulation and incomplete knowledge of the reactions of nervous tissue to anoxia." The recent summary by Shenaq and Svensson 2 concludes that identification and reimplantation of critical intercostal arteries, antioxidants, and spinal cord cooling are the most promising strategies for cord preservation and that presently there is no intervention available to reduce risk of paraplegia in these patients. In 1990 we reported reversal of

2 JOURNAL OF VASCULAR SURGERY Volume 19, Number 2 Acher et at. 237 Table I. Distribution of patients by Crawford type and clinical presentation Crawford type Type I Type II Type III TypeW TA Total Elective Acute 7 12 Total Dissection neurologic deficits by use of intravenous naloxone in two patients who underwent cerebral spinal fluid drainage (CSFD) and the subsequent significant reduction in deficit rate with the combined use of naloxone and CSFD.3 We concluded then that endogenous opiates and opiate receptors play a significant and underappreciated role in the development of spinal cord ischemia. This report details our continued experience with the use of naloxone and CSFD for prevention of neurologic deficits in patients undergoing thoracic aortic replacement. PATIENTS AND METHODS One hundred sixteen patients underwent surgical repair of89 thoracoabdominal aneurysms (TAA) and 27 thoracic aneurysms (TA) from 1983 through One hundred ten patients survived long enough for evaluation of neurologic function. Intraoperative or early postoperative death occurred in six patients. Cause of death in the six patients was hemorrhage in four, stroke in one, and myocardial infarction in one. Follow-up information was obtained in 100% of patients. The mean follow-up time was 32 ± 2.6 months (median 26 months). This report details the clinical and neurologic outcomes in these 110 patients. T AAs were classified according to Crawford's scale of aortic involvement (Table I): type I, the entire descending thoracic aorta to the celiac artery; type II, most of the descending thoracic aorta and the abdominal aorta including visceral and renal arteries; type III, the distal thoracic aorta and most of the abdominal aorta including visceral and renal arteries; and type IV, all of the abdominal aorta up to and including the celiac artery. TAs were a heterogenous group that included traumatic aneurysms and Debakey type III dissections requiring short grafts for repair. Cause in these no cases was atherosclerosis in 93 (84.5%) patients, trauma in 10 (9%), mycotic in 5 (4.5%), lupus in one patient, and Takayasu's disease in 1 patient. Seventy-nine patients (68%) were male. The mean age was 66 years (range 16 to 86). Twenty-seven patients (25%) had previous myocardial infarction; 17 (15%) had undergone previous coronary artery bypass. Redistribution or a fixed defect was present in 18 (44%) of the 41 elective patients who had preoperative thallium stress testing. Significant aortic or mitral valve disease was present in 13 (54%) of 24 patients who underwent cardiac echocardiography. Four of these patients had ejection fractions less than 30%. Thirty-three (30%) had undergone previous aortic surgery (PAS). The serum creatinine level was greater than 1.5 in 40 (35%) patients; four patients underwent long-term dialysis before surgery. Two patients had previous kidney transplants. At surgery all patients had radial artery and pulmonary artery thermodilution catheters for hemodynamic monitoring and received methylprednisolone (30 mg/kg), mannitol (12.5 gm), moderate hypothermia (32 0 to 35 0 C) during operation, and glucose controlled to less than 230 mg/dl as adjuncts to reduce spinal cord ischemia. Moderate hypothermia was achieved with ambient temperature control, cooled intravenous solutions, and no heated humidifier in the ventilator circuit. The strategy for selecting additional spinal cord protective therapies was to choose the most promising from the experimental literature that could be practically applied without risk to the patient. CSFD was introduced in Naloxone was added in 1988 after failure of CSFD to prevent neurologic deficit. Naloxone was administered as a continuous intravenous infusion at 1 J.1g/kg/hr, started before induction and continued for 48 hours after surgery. Thiopental was added in 1989 without a deficit event for its ability to reduce spinal cord metabolism 4 because it was not possible to drain cerebrospinal fluid (CSF) in all patients. Thiopental was administered to maintain burst suppression on electroencephalography immediately before and during aortic occlusion (average dose 32 mg/kg). Anesthetic technique consisted of high-dose fentanyl, benzodiazepine, and neuromuscular blocking drugs. Nitroprusside, nitroglycerin, and betablockers were used to reduce heart strain and control blood pressure during operation. Dopamine and

3 238 Acher et al. JOURNAL OF VASCULAR SURGERY February 1994 Table II. Variables analyzed for deficit risk Sex Age Preoperative serum creatinine (mg/d) Postoperative serum creatinine (mg/dl) Renal revascularization PAS Previous CABG Aortic occlusion time Nitroprusside time Nitroprusside dose Nitrogylcerin time Nitroglycerin dose Volume replacement Preocclusion temperamre Postrelease temperamre PAP MAP CVP Arterial P0 2 Arterial ph CI Group (A,B) Thiopental Amrinone Visceral revascularization Extent of aortic replacement CABG, Coronary artery bypass grafting. The hemodynamic variables PAP, MAP, CVP, and CI were measured before, during, and after aortic occlusion. Arterial P0 2 and ph were measured at frequent intervals before, during, and after aortic occlusion. Temperamre was measured just before aortic occlusion and after aortic cross-clamp release. Dosage and time of administration for nitroprusside and nitroglycerin are the total intraoperative time these drugs were given and the maximum dose/minute used. Amrinone, thiopental, PAS, renal or visceral revascularization, and CABG were dichotomous variables (yes or no). dobutamine were used for inotropic support when necessary. This technique changed significantly in 1988 with the use of amrinone (average dose 0.8 mg/kg), administered before aortic occlusion to reduce blood pressure without large doses of nitroprusside. With the introduction of thiopental in 1989, it became apparent, after some experience, that the use of thiopental and amrinone together eliminated the need for nitroprusside (hypertension from aortic occlusion has been treated in all patients since 1991 with amrinone and thiopental and without nitroprusside). Spinal fluid was drained during surgery with a 19-9auge lumbar catheter, and spinal fluid pressure was monitored manometrically and kept below 10 mm Hg during aortic occlusion. An average ofl 00 ml (range 20 to 220 ml) of spinal fluid was drained. In the last 12 patients we continued to monitor CSF pressure for the first 48 hours after operation but did not drain fluid as the CSF pressure increased. Surgical technique consisted of simple aortic cross-clamping and graft inclusion without bypass or shunts. Patients were not given heparin. Intercostal and lumbar arteries were not reimplanted. Before 1986 intercostal and lumbar arteries were oversewn after the aortic graft was placed; after 1986 they were oversewn before placing the aortic graft. Whenever the renal artery orifices were accessible, renal cooling was done by infusing each kidney with 300 to 400 ml of Ringer's lactate (4 C) containing 12.5 gm of mannitol and 1000 units/l of heparin. Since 1985 postoperative analgesia has been provided by meperidine (25 mg intravenously each hour as needed). Before 1985 morphine was used for postoperative pain control but was discontinued because irreversible paraplegia occurred in one patient 5 minutes after a 10 mg intravenous dose of the drug. Patients were divided into two groups for analysis of neurologic deficit risk. Group A (61 patients) had both intraoperative naloxone and CSFD, and group B (49 patients) did not have combined naloxone and CSFD. Group B was a heterogenous group composed of 13 pat.ients with CSFD alone, 8 with naloxone alone, and 28 with neither naloxone nor CSFD. The other variables analyzed for deficit risk are listed in Table II. Statistics. Paired and two-sample t test, contingency tables with Fisher's exact test, repeated measures analysis of variance and multiple logistic regression analysis were used to analyze variables for deficit risk. Log rank test and proportional hazards analysis were used to evaluate survival and significant factors for risk of death. RESULTS Twelve (10.9%) patients had postoperative neurologic deficits. One deficit occurred in group A and 11 in group B (p < 0.001).* By univariate analysis the variables acute status, dissection, type II or group B classification, and use of thiopental were significant for deficit risk (Table III). There was no significant difference between groups A and B for age, serum creatinine level, sex, aortic occlusion time, extent of aortic replacement, or acute presentation; patients in group A underwent more renal revascularizations (Table IV). With a multiple logistic regression analysis, only acute, type II, and group B classifica- *The one deficit in group A was delayed and occurred 6 days after operation during the first hemodialysis in a patient with an acute type II T AAA who had hypotension caused by a combination of intravenous hydralazine (60 mg given over a 4-hour period) and dialysis.

4 JOURNAL OF VASCULAR SURGERY Volume 19, Number 2 Acher et al. 239 Table III. Significant variables by univariate analysis for deficit Confidence interval Fisher's exact Variable Category NO Deficits p value Odds ratio Low High Acute N Y Type II N Y 33 8 Thiopental N Y 59 2 Dissection N Y 19 5 Group A B Table IV. Statistical difference between groups A and B Variable Group A Group B p Value Two-sample ± test p value No. men 65.6% (40) Crawford type Type I 14.8% (9) Type II 31.1% (19) Type III 9.8% (6) Type IV 24.6% (15) TA 19.7% (12) Acute 41% (25) Dissection 14.8% (9) Renal revascularization 39.3% (24) Age 65.5 Preoperative serum creatinine (mg/dl) 1.6 Aortic occlusion time (min) % (34) 20.4% (10) 28.6% (14) 12.2% (6) 14.3% (7) 24.5% (12) 45% (22) 20% (10) 14.3% (7) There was no statistical difference between groups A and B for the above variables except for the number of renal revascularizations. tion maintained significant effect for risk of deficit (Table V).t Aortic occlusion time, nitroprusside infusion time and dose, temperature, blood loss, and hemodynamic variables (including mean arterial pressure [MAP]) did not have a significant effect.:!: Eight of the 12 deficits occurred in the 33 patients with type II TAAs (1 in group A and 7 in group B, p < ). Ten of the 12 deficits occurred in the 47 surviving patients with acute aneurysms (1 in group A and 9 in group B [p < ]). Performing the same regression analysis on these subcohorts (patients with acute and type II aneurysms) confirmed the significance of group B, extent of aortic tstatistically we cannot separate the individual effects of thiopental, CSFD, and naloxone within group A, which means from an analysis perspective these variables define group A. However, naloxone reversed deficits in two patients not treated with thiopental who had CSFD and the only immediate deficit since starting naloxone was in a patient with acute type I aneurysm who had thiopental but did not have CSFD (group B). tit is important for the reader not to conclude that nonsignificance implies the variable has no biologic effect, only that the significant variables are more important than the nonsignificant ones. replacement, and acute presentation as the primary factors for deficit risk (Table VI). None of the other variables measured had a significant effect in these patient subsets. These regression analyses strongly support the protective effect of the combined use of CSFD and naloxone and support clinical observation that the amount of aorta replaced and acute presentation (dissection or rupture) are the most significant risk factors for development of a neurologic deficit. To further test the validity of our analysis we developed a predictive formula for the deficit risk based on Crawford's risk coefficients for extent of aortic involvement and clinical presentation. 5-7 Our predictive formula is: Estimated number of deficits (E) = [( (C 1 + C 2 )/(total number of patients)) x 0.15) x E 1 ] + E 1, where El = [O.lC I + 0.2C OSC C 4 + O.OlTA] + [(number acute + number dissections) x 0.3]. C is the number of patients in that Crawford group: ' The factors within this equation account for clinical presentation and number of patients at high risk in

5 240 Acher et at. JOURNAL OF VASCULAR SURGERY February 1994 Table V. A, Multiple logistic regression analysis for risk of deficit with a backward elimination method Parameter Standard Wald Variable est. er chi-square p Value Odds ratio Intercept Acute Type II Group (A) Only acute, type II, group A maintained significance for deficit risk (The same result was obtained with a forward stepwise analysis and with all of the significant univariate factors in the model.) Use of quadratic terms and multiplicative interactions in our analysis were never statistically important so for brevity they were not included. Patients in group B were 50 times more likely to have a deficit than patients in group A. Table V. B, Odds ratios and p values of variables in logistic regression for deficit adjusted for the variables acute and type II Confidence interval Variable p Value Odds ratio High Sex Age Preoperative creatinine level Renal revascularization PAS CABG Occlusion time Nitroprusside time/dose Nitroprusside (YjN) Nitroglycerin time/dose Volume replacement Preocclusion temperature Postrelease temperature PAP I PAP 2 PAP 3 MAP I MAP2 MAP3 CVP I CVP 2 CVP 3 1 P0 2 phi PO z 2 ph z CII Cl z Cl CARG, Coronary artery bypass grafting. All dichotomous variables were coded to 0,1. For sex male = 1, for y (yes), n (no) variables y = 1. The odds ratios indicate the deficit odds of y relative to n. For example, subjects for which nitroprusside = y were 2.8 times more likely to have a deficit as for nitroprusside = n. Thiopental was too highly correlated with group A to be estimated. predicting neurologic deficit rate. We applied this predictive formula to 16 published TAA series that classified aneurysms according to Crawford's criteria and clinical presentation (Fig. 2 and Table VII). 3,6,8-20 The strong predictive power of this model (correlation coefficient of 0.997) supports the reliability of our observations that the extent of aortic replacement and clinical presentation are the most significant factors for risk of deficit. The predictability of deficit rates across series supports the conclusion that neurologic outcomes are largely operator independent. When this predictive formula is applied to our data, group B had the predicted number of deficits and group A had fewer deficits than predicted. This

6 JOURNAL OF VASCULAR SURGERY Volume 19, Number 2 Acher et al. 241 Temperature Temperature p= p= Pre Aortic Occlusion Arterial ph Post Occlusion fa+l ~ Pre Occlusion Post Occlusion Arterial ph p= ' ;=----- Pre Aortic Post Occlusion Occlusion Mean Arterial Pressure (MAP) 76-' Pre Aortic Occlusion During Aortic Occlusion Post Aortic Occlusion p= Pre Occlusion Post Occlusion 7.20 Mean Arterial Pressure 90 (MAP) p= L76 Pre Occlusion During Occlusion Post Occlusion Fig. 1. A, With repeated measures ANOVA patients with acute aneurysms were warmer, had acidosis, and had lower blood pressure than patients undergoing elective procedures. B, However, patients in group A and B had no significant difference in these variables. These physiologic data do not account for significant difference in number of deficits between patients with acute aneurysms (10 deficits) and patients undergoing elective procedures (2 deficits) or between acute group A (1 deficit) and B (9 deficits). analysis supports our conclusion that group A (combined use of CSFD and naloxone) had substantially fewer deficits than expected and improved results for deficit compared with group B. Patients with acute aneurysms were warmer, had acidosis, and had a lower MAP than the elective patients (Fig. 1, A), which could be a plausible explanation for the increased risk of deficit in this group. However, within the acute cohort, group A and B were not different for temperature, ph, or MAP (Fig. 1, B), which does not explain the significant difference in deficit rates between acute group A and B (one patient in group A and nine patients in group B had deficits). Only two (3%) of 63 elective patients had a deficit. No deficits have occurred in this group of patients since This elimination of deficit in elective patients coincides with the change in surgical technique to oversewing of intercostal and lumbar arteries before placing the aortic graft and the elimination of morphine as a postoperative analgesic. In elective patients there was no statistical difference between groups A (0) and B (2) (p > 0.17) for neurologic deficit. Postoperative dialysis was required in three patients (2.7%), all with acute aneurysms (1 of these 3 did not recover renal function). Two of the four patients undergoing dialysis before operation had renal revascularization and recovered renal function after operation. The mean length of hospitalization was 20.5 days for all patients. Patients with a deficit had significantly longer hospitalizations (46 days),

7 242 Acher et al. JOURNAL OF VASCULAR SURGERY February % Confidence Bands 160'---~ ~~~ CI) E ~ 80 w o o Actual Fig. 2. Bivariate plot of actual versus estimated number of deficits in 16 series oftaa repair. Very high correlation (correlation coefficient 0.997, p < 0.001) and no statistical difference between actual and estimated (paired t test p = , mean difference = 0.059) number of deficits lend strength to our conclusions that group A had significantly improved results for risk of deficit over group B and that clinical presentation and extent of aorta replaced are primary factors for deficit risk. Table VI. Multiple logistic regression for subgroups of acute, type II, and group B Wald chi-square p Value Odds ratio Acute only variable Intercept Type II Group A Type II only variable Intercept Acute Group A Group B only variable Intercept Type II Acute Multiple logistic regression for subgroups of acute, type II, and group B confirms the significance of clinical presentation and extent of aorta replaced as the primary factors for risk of developing a neurologic deficit. Even in these smaller cohorts, patients in group A have significantly less risk of deficit than patients in group B. and this accounts for the increased length of stay in group B (18 days for group A; 23 days for group B). Eighty-eight patients (76%) were still alive at followup. All eight (6.9%) perioperative deaths occurred in patients with acute aneurysms. With a proportional hazards analysis for survival, the variable deficit was the primary factor (p < 0.01) accounting for the difference in survival between groups A and B. Of the seven patients with paraplegia (the remaining five had paraparesis), only one survived longer than 18 months. DISCUSSION There is widespread confusion about neurologic deficit rates in TAA repair because reports do not focus on the relative risk of the population being treated. Until his death Dr. Stanley Crawford 5-7 had accumulated most of the world experience in TAA

8 JOURNAL OF VASCULAR SURGERY Volume 19, Number 2 Acher et al. 243 Table VII. Data from all recent series of TAA with actual and estimated number of deficits Series Type I Type II Type ill Type IV TA Dissection/acute El Actual Estimated Archer * Hollier * Keiffer lo Svensson! Cunningham 12t COX! de Mol Pokela! Vaccaro l Golden l Cambria! Hollier l7 1988t Schmid~o Williams l Group A Group B Crawford Crawford * In these series only patients without deficit reducing protocols were used for calculation. tin these series not all patients were classified by Crawford criteria, but enough information about extent of aorta replaced was available to make a reasonable guess as to Crawford type. If Crawford's data and our recent data are excluded, the correlation coefficient for estimated versus actual is With Crawford's data the correlation coefficient is In patients in group A actual deficits are much lower than estimated. treatment, and his extensive and detailed reporting of deficit risk by extent of aortic replacement and clinical presentation serves as a reasonable estimate of expected neurologic deficit rates. Our predictive model is an attempt to quantify expected deficits more precisely in a given series of patients on the basis of the risk of the population being treated. This is especially important when evaluating reports with small numbers of patients, which purport to show improved neurologic outcomes. If the control group in a given series has significantly more deficits than predicted, based on the clinical presentation and aneurysm extent, conclusions about effectiveness of interventions are less convincing. The small size of the subsets of patients in group B (naloxone only, CSFD only, or neither) precludes statistical analysis. However, our predictive model can be used to evaluate these subsets in group B (Fig. 3). These subgroups behave consistently for deficit risk, and, despite small numbers, each has approximately the predicted number of deficits. In contrast, in group A the model predicts substantially more deficits than actually occurred. This suggests that the combined effects of naloxone and CSFD provide more protection than each treatment alone. Much emphasis has been placed on identifying and reimplanting the greater radicular artery with the hope of reducing ischemic injury to the cord. 2,l9,21 Reimplantation has not prevented neurologic deficits, and in a recent series that attempted selective reimplantation, the deficit rate was as our model would predict. 19 Our patients did not have intercostal or lumbar reimplantation, and in patients undergoing elective procedures deficit rates dropped to zero coincident with oversewing intercostal arteries before graft placement (theoretically reducing embolization and the sump effect of open backbleeding vessels). Even without intercostal reimplantation, group B had the predicted number of deficits (11 actual versus 14 predicted), whereas group A, with 15 predicted deficits, had only one. Hollier's patients who did not have multimodality therapy for spinal cord protection but did have intercostal reimplantation had the predicted number of deficits. This is a powerful observation for understanding the dynamics of anterior spinal artery blood flow, and it supports our view that other factors are at least as important as interruption of the greater radicular artery in the pathogenesis of spinal cord ischemia and infarction. Experimentally CSFD has consistently reduced the occurrence of neurologic deficits produced by aortic occlusion The accepted mechanism of action is an increase in relative spinal cord perfusion pressure by reducing CSF pressure. 27,28 Clinical experience, however, has not supported the benefit of CSFD alone in reducing neurologic deficit rates. The randomized trials of Crawford 6 and Svenson, 11 although not demonstrating benefit, were flawed because they limited the amount of CSF removed and therefore failed to control CSF pressures. However,

9 244 Acher et at. JOURNAL OF VASCULAR SURGERY February Group A UJ IJ 15 8 UJI/) lin 25tb 6 zo NO# ACTUAL DEFICITS Fig. 3. Plot of actual versus predicted number of deficits for group B subgroups and group A. By our predictive model group B subgroups: naloxone only, CSFD only, and neither CSFD or naloxone were consistent with each other for deficit risk. Group A had significantly fewer deficits than predicted. in our previous, 3 and Hollier's9 more recent experience when CSF pressures were controlled, there was also no reduction in deficits with CSFD alone. Hollier's recent emphasis on multimodality therapy is designed to control factors that may reduce the efficacy of CSF drainage. Although his initial results are encouraging (0 actual and 5 predicted deficit) they have not yet reached statistical significance because of the relatively low risk to this elective patient population. Animal studies have shown that nitroprusside has a deleterious effect on spinal cord blood flow during aortic occlusion Further studies have shown that large doses of nitroprusside reduce the efficacy of CSFD.32 This deleterious effect of nitroprusside may explain the apparent contradiction between clinical reality and compelling experimental data for the beneficial effects of CSFD. Our use of nitroprusside has markedly decreased since the introduction of amrinone and thiopental. However, 80 of our patients did receive nitroprusside, and it was not a significant variable for deficit in our analysis. Patients diagnosed with acute dissection or rupture have a significantly higher risk of deficit than patients undergoing elective procedures with the same extent of aortic involvement. In our multiple logistic regression model, besides the group variable, only acute status and type II classification maintained significance for deficit risk. Although it is assumed that hemodynamic (hypotension) or mechanical factors (interruption of intercostals by dissection) explain this increased risk in patients with acute aneurysms, the data to support this assumption is weak or nonexistent. Our patients with acute aneurysms were warmer and had a lower MAP than patients undergoing elective procedures, but these variables and others that might influence spinal cord perfusion, such as aortic occlusion time, use of high doses of nitroprusside, MAP, central venous pressure (CVP), pulmonary artery pressure (PAP), cardiac index (CI), and ph, did not have significance in our analysis and were no different between acute groups A and B. Our multiple regression analysis for neurologic deficit in all patients with acute aneurysms identified group B and type II classification as the only significant variables. The absence of an explanation for the increased risk in patients with acute aneurysms, in spite of a wealth of measured physiologic parameters, supports the existence of a factor or factors that are independent of the hemodynamic and mechanical parameters and have not been previously considered or measured in these patients. Severe preoperative pain and stress, unique to

10 JOURNAL OF VASCULAR SURGERY Volume 19, Number 2 Acher et al. 245 patients with acute aneurysms, are factors that have not been considered previously in the pathogenesis of spinal cord ischemia. Pain is known to stimulate endogenous opiates (enkephalins, endorphins, and dynorphins) and other neurotransmitters such as substance P These same neurotransmitters have demonstrated negative effects on motor neuron function and spinal cord blood flow, which are reversible with naloxone Systemic 13 endorphins increase during surgical stress and shock; increased spinal fluid endorphin levels may be a specific response to spinal cord ischemia and pain independent of systemic levels. 45 De Riu et al. 46 showed that in dogs, plasma and spinal fluid endorphin levels are independent of each other and that spinal fluid 13 endorphin levels are increased during and for 36 hours after thoracic aortic surgery. The negative effects of opiates and other neurotransmitters may be especially devastating to the ischemically injured neuron, leading to cell death. The two consecutive patients we reported who had reversed neurologic deficits after they received a very low dose of naloxone were admitted with acute aneurysms and received morphine for preoperative pain control. The extremely small dose of naloxone required to reverse the deficits in these patients and our subsequent significant deficit reduction by the addition of naloxone to CSFD implicates the opiate receptors as a possible critical action site. The described enhancement of spinal cord blood flow with naloxone and other endorphin receptor antagonists is not well understood but may be the mechanism of action. Naloxone is a receptor antagonist for mu, kappa, delta, and epsilon receptors. 47 The fact that such low doses of naloxone have such a profound effect without reversing analgesia may implicate the mu 2 receptor, which has been associated with narcotic-induced respiratory depression.48 However the delta and kappa receptors for dynorphins and enkephalins have more clearly demonstrated spinal organization and the toxicity of dynorphins on spinal motor neurons has been demonstrated in animal models. 49,5o Naloxone also has specificity for other receptor sites (substance P) that may playa role in cell injury. 51 From our results and data analysis We conclude that anterior spinal artery blood flow is adequate to prevent spinal cord infarction during thoracic aortic occlusion if cerebral spinal fluid is drained to improve spinal cord perfusion pressure and opiate antagonists are used to negate the deleterious effects of exogenous or endogenous opiates on spinal cord blood flow and motor neuron survival. There are undoubtedly other factors at play in the complex cascade of events leading to motor neuron death. Even with peri operative protection the spinal cord is still vulnerable to extreme circumstances as attested by the late deficit in group A. The protective effect of naloxone and CSFD we have described is simply another clue that may increase our understanding and control of the pathophysiologic condition of spinal cord ischemia. We acknowledge Dennis Heisey, PhD, Department of Information Technology, for his work on the statistical portion of this study. REFERENCES 1. Adams HD, Van Geertruyden HH. Neurologic complications of aortic surgery. Ann Surg 1956;144: Shenaq SA, Svensson LG. Review Article. Paraplegia following aortic surgery. J Cardiothorac Vasc Anes 1993;7: Acher CW, Wynn MM, Archibald J. Naloxone and spinal fluid drainage as adjuncts in the surgical treatment of thoracoabdominal and thoracic aneurysms. 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11 246 Acher et al. JOURNAL OF VASCULAR SURGERY February Cox GS, O'Hara pj, Hertzer NR, Piedmonte MR, Krajewski LP, Beven EG. Thoracoabdominal aneurysm repair: a representative experience. J VAse SURG 1992;15: Pokela R, Tarkka M, Lepojarvi, Nissinen J, Karkola P, Kairaluoma MI. Surgery of thoracoabdominal aneurysms. Eur J Cardiothorac Surg 1989;3: Hollier LH, Symmonds JB, Pairolero PC, Cherry KJ, Hallett JW, Gloviczki P. Thoracoabdominal aortic aneurysm repair: analysis of postoperative morbidity. Arch Surg 1988;123: Cambria RP, Brewster DC, Moncure AC, Ivarsson B, Darling C, Davison K, Abbott WM. Recent experience with thoracoabdominal aneurysm repair. Arch Surg 1989;124: Williams GM, Perler BA, Burdick JF, et al. Angiographic localization of spinal cord blood supply and its relationship to postoperative paraplegia. J VAse SURG 1991;13: Schmidt CA, Wood MN, Gan KA, Razwuk AI. Surgery for thoracoabdominal aortic aneurysms. Am Surg 1990;56: Svens~on LG, Patel V, Robinson MF, et al. 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12 JOURNAL OF V ASeULAR SURGERY Volume 19, Number 2 Acher et ai. 247 DISCUSSION Dr. Larry H. Hollier (New Orleans, La.). Six years ago we reported our initial experience with spinal fluid drainage as an adjunct to prevent spinal cord injury. Two years later, after more clinical experience, we postulated that the pathophysiology of spinal cord ischemia could be best understood as the interrelated variables of the severity of the ischemic event, the rate of neuronal metabolism during the time of ischemia, and the secondary injury from activated leukocytes, oxygen-derived free radicals, cord edema, and other aspects of the reperfusion phenomeno,n. This study supports our theory, because the authors showed a reduced instance of paraplegia in those patients who had systemic cooling, spinal fluid drainage, and naloxone, thus reducing neuronal metabolism and minimizing some of the deleterious effects of the reperfusion phenomena. In my experience with more than 200 TAA repairs, the use of adjunctive measures without naloxone has resulted in an overall neurologic deficit rate of 4.4%, and in 87 patients with type I and II TAA, a deficit rate of only 5.7%. More importantly, however, the only patients in my series who had paraplegia or paraparesis were those who, for technical reasons, had incomplete intercostal artery reimplantation. What impressed me in this study is that Dr. Acher reportedly oversewed all intercostal arteries. This is surprising, because we have generally accepted the failure to reimplant critical intercostal arteries as something that would result in a high instance of paraplegia in type I and II TAAs. Thus to have the overall results you reported, he seems to have a lower incidence of type II aneurysms, although that's not what we see in this study. Would you define the number of type I and type II aneurysms in the patients in group A1 Also, was there any selective reimplantation in patients with type I and type II aneurysms1 Also, because cooling has been shown to be the most effective adjunct in reducing neuronal injury, and in your study you state that your protocol includes moderate hypothermia of 32 to 35 C, do you really believe that naloxone adds any additional protection1 Finally, naloxone and every other adjunctive agent is theoretically effective because it either improves collateral flow to the cord during clamping, or it minimizes the deleterious effects of ischemia, thus allowing the surgeon more time to sew in,the graft and to reimplant any critical intercostal arteries. lkcause you routinely oversewed intercostal arteries, they clearly were not critically needed in those patients. Were any adjunctive measures responsible for continued cord function in your patients if they didn't have critical intercostal arteries, or was it simply that the patient mix was at low risk1 If indeed intercostal artery reimplantation is not needed in type II T AA, I don't believe that we understand the mechanisms of paraplegia. Dr. Lars G. Svensson (Boston, Mass.). With Dr. Crawford's data, we did a similar analysis trying to predict the incidence of paraplegia or paraparesis with a logistic regression stepwise model. We, however, weren't that accurate. We took our patients and first did the study, and then did a retrospective, putting the patients through the model again, and we only had a 60% accuracy rate with the variables we used. My question concerns your incidence according to extent of aneurysms. In Dr. Crawford's 1500 patients, one quarter of the patients had type I aneurysms and one quarter had type II aneurysms, and I noticed in your study that 36% had type II aneurysms, and I was wondering whether this was a reflection of your referral pattern, that you have perhaps a larger group of type II aneurysms. Would you comment on Dr. Crawford's classification of aneurysms, because on the basis of our patients, we suspected that the patients who had a type II or type I aneurysm beginning in the middescending aorta behaved sometimes more like a type III rather than a type I or II aneurysm developing or originating at the subclavian artery. Had you noticed any difference in behavior of these aneurysms1 Did they behave more like type III aneurysms1 Should we subclassify those aneurysms1 You have raised a very important subject, and that is that the cause of paraplegia or paraparesis is clearly multifactorial, and use of multimodality techniques or trying to reduce the incidence of paraplegia and paraparesis is the way to go. And you used two techniques, but I noticed also in conjunction with your CSF drainage and use of naloxone, you used many others. In previous reports it hasn't been clear that CSF drainage alone, or naloxone in patients with spinal cord injuries in the multicensus study, was effective, would you speculate on the mechanism of action of the protective effect1 I also notice you did not use any distal perfusion techniques, and in Dr. Crawford's 1500 patients, and in 832 descending aneurysms we recently analyzed, the incidence of kidney failure was reduced by 50% by distal perfusion, and in the patients who had aortofemoral bypass with cross-clamp times longer than 40 minutes, the incidence of paraplegia and paraparesis was reduced by aortofemoral bypass; would you comment on that, and your cross-clamp times, particularly because you did not implant any intercostal arteries. Dr. G. Melville Williams (Baltimore, Md.). It seems inconceivable to me that you could get by treating every patient with a type II TAA ignoring intercostal arteries. Doing studies trying to identify the origin of the anterior spinal artery, or the artery of Adamkiewicz, I have been impressed with the variability of the size of this contribution that comes from the intercostal arteries. In some individuals you can't find this artery at all. Under those circumstances collateral vessels that were already developed

13 248 Acher et ai. JOURNAL OF VASCULAR SURGERY February 1994 from the cervical origin to the anterior spinal artery have a huge contribution to the anterior spinal artery, which goes both proximal and distal when the anastomosis between this intercostal branch enters the spine. And it's in that particular type of patient that there is a very high risk of paralysis. I urge a little caution in intercostal neglect, although I agree with you, that most of the time when we find the artery, it's a very small contribution to the spinal cord. And in 40% of the patients, we can't find any contribution to the spinal cord. How many 3B dissections are included in the type II aneurysm because it's in the 3B dissections where the highest risk of paralysis occurs because of the greatest number of open intercostal vessels? Dr. Charles W. Acher. Both groups A and B were high-risk patient populations. Group A had 31% type II aneurysms and 41 % acute presentation. Group B had 28% type II aneurysms and 45% acute presentation. Patients classified as type II had aneurysms that originated in the proximal third of the thoracic aorta. We reviewed the aneurysms in the naloxone, spinal fluid tteatment group to see if they were any different than aneurysms in the nontreatment group for extent of aortic replacement and the presence of dissection. We found no difference. We cannot explain the difference in results based on a difference in the extent of aortic replacement or the complexity of the aneurysm between groups A and B; both populations had the same paraplegia risk. No distal perfusion techniques were used. Cross-clamp time was 46 minutes in group A and 43 minutes in group B. There was no reimplantation of intercostal arteries in either group of patients or in any type of aneurysm. All intercostal arteries were oversewn. A significant aspect of our experience is not reimplanting or making any attempt to preserve intercostal blood flow. Even when thoracic aortic blood flow is interrupted, in most patients the spinal cord has excellent collateral blood flow, which even at reduced perfusion pressures protects it during aortic occlusion. If we do something to decrease that collateral flow, such as allow spinal fluid pressure to increase too much, or allow intercostal arteries to bleed during graft placement, shunting blood away from the spinal cord, we put the cord at risk for injury. Over-sewing the intercostal arteries as soon as possible after aortic occlusion increases the perfusion pressure in the collateral bed during those critical first few minutes after aortic occlusion when perfusion pressures would be significantly reduced if the intercostal arteries were left open. We identified naloxone as a critical intervention because it reversed deficits in the postoperative period in two patients who had spinal fluid drainage during operation. Both these patients awoke with deficits and then were given naloxone and had reversal of their deficit within 2 to 6 hours. From that time on, we used naloxone and spinal fluid drainage during operation and continued naloxone after operation. With the combination of naloxone and spinal fluid drainage, we had no immediate deficits and only one delayed deficit in treating the high-risk population that we encountered over the last 5 years. We have had immediate deficits in patients who had spinal fluid drainage alone and patients who had the combination of naloxone and thiopental without spinal fluid drainage. We too believe that temperature is a factor in spinal cord injury in these patients; however, in our analysis, it was not as important as naloxone and spinal fluid drainage. Patients with acute aneurysms were warmer, had acidosis, and had a lower mean arterial pressure and slightly higher cardiac index than elective patients. This difference might be an explanation for the higher incidence of paraplegia in patients with acute aneurysms. However, if we compare just the acute patient subgroup as we did in our multivariate analysis, we see that there is no significant difference in temperature, ph, mean arterial pressure, and cardiac index between group A and group B. Yet in the patients with acute aneurysms, nine deficits occurred in group B and one in group A. There was no difference in temperature and hemodynamic variables between acute group A and group B patients to explain this difference in outcome. We believe that exogenous and endogenous opiates are an underappreciated factor that potentiates the ischemic insult to the cord in the face of reduced spinal cord perfusion pressures. The cellular mechanism of action is poorly understood at the receptor level, but there is ample experimental evidence to indicate that opiates have a profound deleterious effect on motor neuron function in the context of an ischemic insult. I would like to comment on the implications of our predictive model. In our analysis, the two most important factors for risk of deficit were extent of aortic replacement and acute clinical presentation. With these two factors alone, in a predictive model, we were able to accurately predict the neurologic outcomes in unrelated series from multiple institutions. This ability to predict outcomes is important in the debate over the effect of various interventions to reduce risk of paraplegia and highlights a very important aspect of general discussion in this area. When we speak of paraplegia rate, it has to be done in the context of the paraplegia risk of that population of patients. This paraplegia risk varies from experience to experience and institution to institution; yet many times when results are reported we fail to accurately define the risk factors of the population under discussion. The reporting of paraplegia incidence out of this context is not very illuminating. This predictive model clearly says that our group A and group B had the same relative risk for neurologic deficit, yet in reality they had markedly different outcomes.

14 JOURNAL OF VASCULAR SURGERY Volume 19, Number 2 Announcement 249 THE E. J. WYLIE TRAVELING FELLOWSHIP OF THE LIFELINE FOUNDATION OF THE SOCIETY FOR VASCULAR SURGERY Guidelines The primary purpose of the Edwin J. Wylie Traveling Fellowship is to provide the recipient with the opportunity to visit a number of excellent vascular surgery centers in the United States and abroad. Though brief, these visits stimulate academic inspiration, promote international exchange, and foster development of fraternal fellowship in vascular surgery. The achievement of these objectives will enhance the development of the fellow's career in vascular surgery. This award is not intended to support specific research interests but rather to assist the fellow in a unique opportunity for travel and professional exchange within established vascular centers in this country and abroad. Eligibility for selection 1. Be under age 40 at the time of the award 2. Have completed a postgraduate vascular training program or have considerable experience in vascular surgery supplemental to surgical training 3. Be committed to an academic career in vascular surgery and have obtained an academic appointtnent in a medical school or freestanding clinic devoted to excellence in medical education 4. Have a demonstrated record of success in pursuing clinical or basic science research sufficient to ensure academic excellence in his or her pursuit of a career in vascular surgery Selection will be made without regard to the candidate's geographic location. Requirements for consideration A candidate submitting documentation for consideration for selection must furnish an up-to-date curriculum vitae, a list of publications, research projects, and current research support, and a list of the centers that he or she wants to visit. Three letters of recommendation are required, including one from the division head and another from the chairman of the departtnent of surgery of the institution in which the candidate holds a faculty appointment. A SOO-word essay describing the objectives of the candidate's travel plans and linking these to his or her career goals must be appended. Report to Committee A report covering your experience should be prepared and forwarded to the chairman of the Fellowship Committee within 3 months of completion of your fellowship travel. This report should be five to eight double-spaced typewritten pages and should summarize your activities during the fellowship. Although factual statements of activities should be included, you are encouraged to place these within an overall context of their impact on your education and maturation. The format of the report and its content should be suitable for consideration by the Committee for publication in the JOURNAL OF VASCULAR SURGERY. Financial support The generosity of W. L. Gore & Associates, Inc., has allowed the establishment of this fellowship. Their graciousness ensures the noncommercial nature of the award and its continuation in years to come. The Wylie Traveling Fellowship of the Educational Foundation of the Society for Vascular Surgery will pay up to $10,000 for expenses of travel, research, and clerical help. The fellowship monies may not be used for other purposes. Application No application forms are required. A letter demonstrating interest in applying for the E. J. Wylie Traveling Fellowship or nominatng a candidate may be sent to the chairman of the Committee. Details of the application should include the materials requested above. The deadline for receiving applications is March 1, Letter of nomination or intent should be directed to Malcolm O. Perry, MD Chairman, E. J. Wylie Traveling Fellowship Committee Department of Surgery Texas Tech University Health Science Center th St. Lubbock, TX 79430