the medical management of patients who have sustained an aneurysmal subarachnoid

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1 CLINICAL STUDIES Jonathan A. Friedman, M.D. Mark A. Pichelmann, M.D. David G. Piepgras, M.D. Jon I. McIver, M.D. L. Gerard Toussaint III, M.D. Robyn L. McClelland, Ph.D. Department of Biostatistics, Mayo Clinic, Rochester, Minnesota Douglas A. Nichols, M.D. Department of Radiology, Mayo Clinic, Rochester, Minnesota Fredric B. Meyer, M.D. John L.D. Atkinson, M.D. Eelco F.M. Wijdicks, M.D. Department of Neurology, Mayo Clinic, Rochester, Minnesota PULMONARY COMPLICATIONS OF ANEURYSMAL SUBARACHNOID HEMORRHAGE OBJECTIVE: Pulmonary complications challenge the medical management of patients who have sustained aneurysmal subarachnoid hemorrhage (SAH). We assessed the frequency and types of pulmonary complications after aneurysmal SAH and analyzed the impact of pulmonary complications on patient outcome. METHODS: We reviewed the records of all patients with acute SAH treated at our institution between 1990 and Three hundred five consecutive patients with an aneurysmal hemorrhage source documented by angiography and treated within 7 days of ictus were analyzed. Outcomes at longest follow-up (mean, 16 mo) were measured by use of the Glasgow Outcome Scale. RESULTS: Pulmonary complications were documented in 66 patients (22%). The pulmonary complications were nosocomial pneumonia in 26 patients (9%), congestive heart failure in 23 (8%), aspiration pneumonia in 17 (6%), neurogenic pulmonary edema in 5 (2%), pulmonary embolus in 2 ( 1%), and other pulmonary disorders in 4 (1%); 11 patients had two pulmonary complications. The incidence of symptomatic vasospasm was greater in patients with pulmonary complications (63%) than in patients without pulmonary complications (31%) (P 0.001), and this association was independent of age and clinical grade at admission (odds ratio, 3.68; P 0.001). Overall clinical outcomes were worse in patients with pulmonary complications (mean Glasgow Outcome Scale score, 3.3) than in patients without pulmonary complications (mean Glasgow Outcome Scale score, 4.0; P ), but pulmonary complications were not an independent predictor of worse outcome when adjusted for age and clinical grade at admission (odds ratio, 1.38; P 0.315). CONCLUSION: Patients who experience pulmonary complications after aneurysmal SAH have a higher incidence of symptomatic vasospasm than do patients without pulmonary complications. This most likely reflects both the failure to maintain aggressive hypervolemic and hyperdynamic therapy in patients with pulmonary compromise and the possible precipitation of congestive heart failure by hypervolemic therapy in patients with preexisting delayed ischemic neurological deficit. Although patients with pulmonary complications have worse overall clinical outcomes than do patients without pulmonary complications, this is attributable to older age and worse clinical grades at admission. KEY WORDS: Aneurysm, Neurogenic pulmonary edema, Pulmonary, Subarachnoid hemorrhage, Vasospasm Neurosurgery 52: , 2003 DOI: /01.NEU F1 Reprint requests: Jonathan A. Friedman, M.D., Joseph 1-229, Saint Mary s Hospital, 1216 Second Street SW, Rochester, MN friedman.jonathan@mayo.edu Received, August 30, Accepted, January 8, Pulmonary complications frequently challenge the medical management of patients who have sustained an aneurysmal subarachnoid hemorrhage (SAH) and may be a significant source of morbidity in SAH patients (6, 9, 10, 15, 24). Better characterization of the specific pulmonary complications that affect this patient population might facilitate improved prevention and treatment. We analyzed our experience with the management of pulmonary complications in a contemporary, consecutive series of patients with aneurysmal SAH. PATIENTS AND METHODS The records of all patients with acute SAH treated at our institution between 1990 and 1997 were reviewed. Three hundred five consecutive patients with an aneurysmal hemorrhage source documented by angiography NEUROSURGERY VOLUME 52 NUMBER 5 MAY

2 FRIEDMAN ET AL. who were treated at our institution within 7 days of ictus were analyzed. Outcomes were measured by one of four unblinded reviewers at longest follow-up (mean, 16 mo; 183 patients had at least 3 mo follow-up; 128 patients had at least 6 mo followup) using the Glasgow Outcome Scale (GOS). Diagnoses of specific pulmonary complications were ascertained as follows. Nosocomial pneumonia was considered to be a clinical pneumonia that developed while the patient was hospitalized. Microbiological confirmation was often available but was not a requisite for this diagnosis. Congestive heart failure was defined as pulmonary edema without an infectious or systemic (e.g., adult respiratory distress syndrome) cause, with characteristic radiographic appearance. Specific cardiac function parameters were not requisite for the diagnosis. The diagnosis of aspiration pneumonia was based on a combination of characteristic clinical, radiographic, and microbiological findings. Neurogenic pulmonary edema (NPE) was considered on the basis of characteristic clinical and radiographic findings in the absence of alternative causes, such as cardiac dysfunction. A cardiologist or critical care specialist confirmed all cases of NPE. Patients in whom the diagnosis of NPE was possible but not definitive were considered not to have NPE. Pulmonary embolus was diagnosed by pulmonary angiogram in one patient and by a high-probability ventilation/perfusion nuclear medicine scan in a second patient. Symptomatic vasospasm was defined as documented arterial vasospasm consistent with new neurological deficits presenting between 4 and 14 days after the onset of SAH and not explained by other causes of neurological deterioration (rebleeding, acute or worsening hydrocephalus, electrolyte disturbances, hypoxia, or seizures). Clinically, vasospasm was categorized as severe, moderate, or absent. Severe symptomatic vasospasm was defined as complete focal deficit or coma. Moderate symptomatic vasospasm was defined as the presence of an incomplete focal deficit or impaired level of consciousness without coma. To determine whether two categorical variables were related, we used 2 tests of independence. To compare patients with and without pulmonary complications on the basis of quantitative variables, we used nonparametric Wilcoxon ranksum tests. Associations between pulmonary complications and the odds of a clinical spasm were investigated by use of logistic regression models. Unadjusted models; models that adjust for age and Hunt and Hess grade; and models that adjust for age, Hunt and Hess grade, and other risk factors are presented. The other risk factors are aneurysm location (posterior versus anterior), hypertension, and external ventricular drainage. All two-way interactions between any pulmonary complication and the other variables were tested for inclusion in the model for a value of P < We present odds ratios and 95% confidence intervals for the effect of any pulmonary complication. An analogous series of models were fit by use of the odds of severe disability (GOS 3) as the response. RESULTS Pulmonary complications were documented in 66 patients (22%) (Fig. 1). The specific pulmonary complications were nosocomial pneumonia in 26 patients (9%), congestive heart failure in 23 (8%), aspiration pneumonia in 17 (6%), NPE in 5 (2%), pulmonary embolus in 2 ( 1%), and other pulmonary disorders in 4 (1%). These other pulmonary complications consisted of unexplained upper-airway edema, apneic spells requiring intubation, adult respiratory distress syndrome of unclear pathogenesis, and spontaneous pneumothorax in the setting of recent ventilation with positive end-expiratory pressure. Eleven patients sustained two separate pulmonary complications. Patient demographics and clinical features are shown in Tables 1 and 2, along with unadjusted associations between presence of pulmonary complications and clinical variables. Older age, worse Hunt and Hess grade at admission, lower Glasgow Coma Scale score, and a history of hypertension were each associated with the development of pulmonary complications in a univariate analysis. The incidence of symptomatic vasospasm was greater in patients with pulmonary complications (63%) than in patients without pulmonary complications (31%) (P 0.001). Aneurysm location (anterior versus posterior circulation) and treatment modality (surgical clipping versus endovascular coil occlusion) were not associated with the development of pulmonary complications, with the exception of a higher rate of nosocomial pneumonia in patients with posterior circulation aneurysms. Overall clinical outcomes at longest follow-up were worse in patients with pulmonary complications (mean GOS score, 3.3) than in patients without pulmonary complications (mean GOS score, 4.0) (P ). There were no significant differences in clinical outcome between the subtypes of pulmonary complications (Table 1). Because clinical condition at admission, age, and other clinical variables were likely to be associated with pulmonary complications, symptomatic vasospasm, and clinical outcome, logistic regression models were constructed to adjust for these FIGURE 1. Pie chart demonstrating distribution of subtypes of pulmonary complications. CHF, congestive heart failure VOLUME 52 NUMBER 5 MAY

3 PULMONARY COMPLICATIONS OF ANEURYSMAL SUBARACHNOID HEMORRHAGE TABLE 1. Pulmonary complications by categorical clinical characteristics a No. of patients Any pulmonary complication (no. [%]) Nosocomial pneumonia (no. [%]) Congestive heart failure (no. [%]) Aspiration pneumonia (no. [%]) No Yes P No Yes P No Yes P No Yes P All subjects (78) 66 (22) 277 (91) 26 (9) 280 (92) 23 (8) 286 (94) 17 (6) Sex Female (79) 40 (21) (91) 17 (9) (92) 15 (8) (96) 8 (4) Male (77) 26 (23) 104 (92) 9 (8) 105 (93) 8 (7) 104 (92) 9 (8) Hunt and Hess grade (92) 8 (8) (97) 3 (3) (95) 5 (5) (100) (79) 19 (21) 79 (89) 10 (11) 82 (92) 7 (8) 87 (98) 2 (2) (68) 19 (32) 52 (88) 7 (12) 51 (86) 8 (14) 54 (92) 5 (8) (54) 16 (46) 30 (88) 4 (12) 32 (94) 2 (6) 26 (76) 8 (24) (78) 4 (22) 16 (89) 2 (11) 17 (94) 1 (6) 16 (89) 2 (11) Aneurysm location Anterior (82) 39 (18) (95) 10 (5) (93) 16 (7) (94) 13 (6) Posterior (70) 19 (30) 52 (83) 11 (17) 58 (92) 5 (8) 61 (97) 2 (3) Both (69) 8 (31) 19 (79) 5 (21) 22 (92) 2 (8) 22 (92) 2 (8) Treatment group Both 5 3 (60) 2 (40) (60) 2 (40) (100) (100) Clip (79) 51 (21) 223 (93) 18 (7) 221 (92) 20 (8) 227 (94) 14 (6) Coil (83) 5 (17) 25 (89) 3 (11) 27 (96) 1 (4) 26 (93) 2 (7) None (72) 8 (28) 26 (90) 3 (10) 27 (93) 2 (7) 28 (97) 1 (3) Hypertension No (83) 29 (17) (94) 11 (6) (94) 11 (6) (95) 8 (5) Yes (72) 37 (28) 117 (87) 15 (11) 120 (91) 12 (99) 123 (93) 9 (7) Acute hydrocephalus No (84) 35 (16) (94) 14 (6) (95) 12 (5) (96) 9 (4) Yes (64) 31 (36) 72 (86) 12 (14) 73 (87) 11 (13) 76 (90) 8 (10) Symptomatic vasospasm No (88) 23 (12) (95) 9 (5) (96) 8 (4) (98) 4 (2) Yes (65) 39 (35) 93 (85) 16 (15) 96 (88) 13 (12) 96 (88) 13 (12) GOS (88) 20 (12) (94) 10 (6) (95) 8 (5) (99) 2 (1) (69) 13 (31) 39 (95) 2 (5) 36 (88) 5 (12) 34 (83) 7 (17) (65) 16 (35) 38 (83) 8 (17) 43 (93) 3 (7) 40 (87) 6 (13) (25) 3 (75) 3 (75) 1 (25) 3 (75) 1 (25) 4 (100) (78) 14 (27) 45 (90) 5 (10) 44 (88) 6 (12) 48 (96) 2 (4) Mean (standard deviation) (1.5) 3.3 (1.5) (1.5) 3.4 (1.5) (1.5) 3.3 (1.6) (1.5) 3.4 (1.1) a Because of the small number of patients with neurogenic pulmonary edema, pulmonary embolus, and other pulmonary disorders, they are not shown separately here. GOS, Glasgow Outcome Scale score. NEUROSURGERY VOLUME 52 NUMBER 5 MAY

4 FRIEDMAN ET AL. TABLE 2. Pulmonary complications by continuous clinical characteristics a Any pulmonary Nosocomial pneumonia Congestive heart failure Aspiration pneumonia complication No Yes P No Yes P No Yes P No Yes P Age (yr) Median Range Hunt and Hess score Median Range GCS on admission Median Range a GCS, Glasgow Coma Scale score. effects (Table 3). The presence of pulmonary complications remained independently associated with the development of symptomatic vasospasm in all models. However, pulmonary complications were not independently associated with poor clinical outcome (GOS 3) in models that controlled for age and Hunt and Hess grade at admission. The clinical data of five patients with a definitive diagnosis of NPE compared with all patients with SAH who did not experience NPE are shown in Table 4. Hunt and Hess grades at admission and Glasgow Coma Scale scores were slightly worse in patients with NPE. The rate of symptomatic vasospasm was substantially higher in patients with NPE than in those without NPE (60% versus 35%). The time to treatment between the groups was not significantly different, with an average of 6.4 days to treatment for patients with NPE compared with 3.7 days for patients without NPE. One patient with NPE died as a result of a postoperative stroke. Clinical outcomes at longest follow-up were not significantly worse in patients with NPE. DISCUSSION Reduction of medical morbidity after SAH is an important potential means of improving overall patient outcomes. Pulmonary complications are among the most common medical sources of morbidity after SAH: our frequency of 22% is consistent with previous reports (9, 10, 24). The three most common complications in our series were nosocomial pneumonia, congestive heart failure, and aspiration pneumonia, which together accounted for 85% of all pulmonary complications after SAH. These complications are typical of pulmonary disorders in critically ill patients in general and probably were not specific to the neurological insult. Continued advances in critical care and pul- TABLE 3. Logistic regression models for associations with pulmonary complications a Variables Symptomatic vasospasm Severe disability (GOS 1 3) OR (95% CI) P OR (95% CI) P Any pulmonary complication 3.79 ( ) ( ) Any pulmonary complication 3.68 ( ) ( ) Age 0.99 ( ) ( ) Hunt and Hess 1.10 ( ) ( ) Any pulmonary complication 3.97 ( ) ( ) Age ( ) ( ) Hunt and Hess 1.00 ( ) ( ) Posterior location 0.60 ( ) ( ) Hypertension 0.61 ( ) ( ) EVD 2.54 ( ) ( ) a GOS, Glasgow Outcome Scale score; OR, odds ratio; CI, confidence interval; EVD, external ventricular drainage VOLUME 52 NUMBER 5 MAY

5 PULMONARY COMPLICATIONS OF ANEURYSMAL SUBARACHNOID HEMORRHAGE TABLE 4. Characteristics of patients with and without neurogenic pulmonary edema a Patients with NPE Patients without NPE Age (yr) (mean) Hunt and Hess grade (mean) Admission GCS (mean) Symptomatic vasospasm (%) 60% 37% Time to treatment (d) GOS (mean) Mortality (%) 20% 16% a NPE, neurogenic pulmonary edema; GCS, Glasgow Coma Scale score; GOS, Glasgow Outcome Scale score. monary medicine in general should therefore have a substantial influence on improving morbidity in patients with pulmonary complications after SAH. In clinical practice, a definitive and objective diagnosis differentiating between subtypes of pulmonary complications is often lacking. Nevertheless, in our opinion, the diagnosis of the experienced clinician combined with the perspective of the investigator examining the entire case and clinical course retrospectively provides an accurate diagnosis in most if not all cases. Interestingly, no specific subtype of pulmonary complication was associated with significantly worse outcome. We found, as have others, that pulmonary complications are associated with worse clinical grade at admission and with older age (6, 9, 10, 19, 24). For nosocomial pneumonias, this can be explained by the need for endotracheal intubation and prolonged intensive care in patients with worse clinical grade at admission. For aspiration pneumonia, aspiration at ictus and prolonged inability to protect the airway are more common in patients with worse initial clinical condition. Patients who experienced congestive heart failure are probably a diverse group, consisting of some patients with preexisting cardiac disease and others with cardiac dysfunction related to SAH or with iatrogenic hypervolemia for the prophylaxis and treatment of symptomatic vasospasm. Because of the strong association between clinical grade at admission, age, and the development of pulmonary complications, these variables must be controlled in logistic regression models to meaningfully analyze the independent relationship between pulmonary complications, symptomatic vasospasm, and outcome. Association with Symptomatic Vasospasm and Clinical Outcome The results of logistic regression analyses of our data suggest that a strong and independent association exists between pulmonary complications and the development of symptomatic vasospasm. There are two possible explanations for this association, both of which are likely to occur over a series of patients. Patients with symptoms of delayed ischemic neurological deficit or at high risk for delayed ischemic neurological deficit were more likely to receive aggressive hypervolemic, hyperdynamic therapy, which may have precipitated congestive heart failure. However, because congestive heart failure accounted for only 35% of pulmonary complications, this cannot be the only, or even the predominant, explanation. A more germane explanation may be that patients with pulmonary complications could not be treated aggressively with hypervolemic, hyperdynamic therapies, thus exacerbating vasospasm and increasing the likelihood of delayed ischemic neurological deficit. Early and aggressive endovascular management of vasospasm with angioplasty and papaverine infusion may be a particularly effective strategy in patients with pulmonary complications after SAH. Despite the independent association with symptomatic vasospasm, the development of pulmonary complications was not independently associated with poor clinical outcome in models that controlled for age and clinical grade at admission. Therefore, the presence of a pulmonary complication should not be a central factor in establishing prognosis or preclude an aggressive management posture for patients with SAH in this setting. Although the presence or absence of a pulmonary complication was not independently predictive of outcome in our study, a complex scale of pulmonary pathology that accounts for radiographic and blood gas findings has been suggested as a predictor of outcome (9). Neurogenic Pulmonary Edema NPE has been described as a consequence of various types of brain injury, including SAH, head trauma, seizures, intracranial hematomas, and stroke (1 3, 7, 18, 22, 27). Theodore and Robin (25) proposed a unifying hypothesis that severe brain injury results in a massive sympathetic discharge, with consequent systemic vasoconstriction and increase in blood pressure, and a relative shift of intravascular volume to the lower-resistance pulmonary vascular beds. This leads to a transient increase in pulmonary artery pressure and subsequent hydrostatic pulmonary edema, called the blast theory. A sudden increase in intracranial pressure, ischemia or trauma to the hypothalamus, or ischemia or mass effect on the medulla have been implicated in initiating the massive autonomic discharge that seems to be a prerequisite to the pulmonary pathology (5, 11, 14, 20). Smith and Matthay (23) also proposed a hydrostatic mechanism in NPE on the basis of early alveolar fluid sampling. Controversy regarding the precise mechanism of edema formation, however, has persisted. Some investigators have hypothesized that the pulmonary edema is a consequence of increased capillary permeability as a result of a direct sympathetic effect on the capillary endothelium rather than an increase in pulmonary artery pressure. This is based on observations of normal pulmonary artery wedge pressures shortly after the neurological insult and the NEUROSURGERY VOLUME 52 NUMBER 5 MAY

6 FRIEDMAN ET AL. finding of protein-rich pulmonary fluid in many patients, indicating primary endothelial damage (17). Although NPE has traditionally been defined as a primary pulmonary abnormality, the role of transient cardiac dysfunction contributing to the pathological picture has been explored. Mayer et al. (16) and Schell et al. (21) found that transient heart dysfunction leading to increased left atrial pressures and subsequent pulmonary hypertension may be a contributing factor in the formation of pulmonary edema in the early stages. Normal wedge pressures may be measured because of a quick recovery of the heart and restoration of normal cardiac output. Later, endothelial damage may predominate, resulting in high protein content in the edema fluid. It is possible that any or all of these mechanisms play a varying role in the formation of pulmonary edema in the individual patient. However, no patient in our series had documented cardiac pathology concomitantly with the clinical manifestations of NPE. NPE after SAH has been associated with poor outcomes and death (8, 16). Although one retrospective study suggested an incidence of NPE complicating fatal SAH of 31% on the basis of clinical criteria and up to 71% in autopsy-reviewed cases, in general, the outcome of NPE after SAH is poorly characterized (26). Crompton (4) and Weir (26) both found a high incidence of NPE in fatal SAH. This finding may be explained in part by the conflicting fluid management paradigms for optimal treatment of aneurysmal SAH compared with NPE and with the severity of the primary cerebral insult. Because most studies of outcome in NPE have been based primarily on autopsy findings of patients who died of intracranial hemorrhage, little is known about the outcome of patients who survive the initial cerebral insult and the best approach to management. On the basis of more recent experience, Yabumoto et al. (27) advocated early and aggressive treatment of the ruptured aneurysm and symptomatic treatment of NPE. Our findings indicate that treatment should not be delayed or withheld in patients with NPE unless the risk of anesthesia is prohibitive. Early operation has been shown to improve outcomes in patients with SAH by reducing rates of rehemorrhage and facilitating aggressive medical management of arterial vasospasm (12, 13). The incidence of symptomatic vasospasm in our patients with NPE was higher than in those without NPE. This is most likely a result of conservative fluid management and use of diuretics to promote adequate oxygenation in these patients. As NPE resolves, hyperdynamic and hypervolemic therapy can be instituted if the aneurysm has been secured. The satisfactory overall outcome we found in patients with NPE contrasts with previous reports and may reflect advances in critical care and pulmonary care medicine as well as improved outcomes with early aneurysm surgery. CONCLUSIONS Patients who experience pulmonary complications after aneurysmal SAH have a higher incidence of symptomatic vasospasm than do patients without pulmonary complications. Although patients with pulmonary complications have worse overall clinical outcomes than do patients without pulmonary complications, this is attributable to older age and worse clinical grades at admission. Patients with NPE may have a more favorable prognosis than previously expected. Early aneurysm treatment and aggressive management of symptomatic vasospasm are warranted in patients with pulmonary complications after aneurysmal SAH. REFERENCES 1. Carlson RW, Schaeffer RJ, Michaels SG, Weil MH: Pulmonary edema following intracranial hemorrhage. Chest 75: , Ciongoli KA, Poser CM: Pulmonary edema secondary to subarachnoid hemorrhage. Neurology 22: , Cohen JA, Abraham E: Neurogenic pulmonary edema: A sequela of nonhemorrhagic cerebrovascular accidents. Angiology 27: , Crompton MR: The pathogenesis of cerebral infarction following the rupture of cerebral berry aneurysms. Brain 87: , Cushing H: Concerning a definite regulatory mechanism of the vaso-motor centre which controls blood pressure during cerebral compression. Bull Johns Hopkins Hosp 12: , Demling R, Riessen R: Pulmonary dysfunction after cerebral injury. Crit Care Med 18: , Ducker TB: Increased intracranial pressure and pulmonary edema: Part I Clinical study of 11 patients. J Neurosurg 28: , Fein IA, Rackow EC: Neurogenic pulmonary edema. Chest 81: , Gruber A, Reinprecht A, Gorzer H, Fridrich P, Czech T, Illievich UM, Richling B: Pulmonary function and radiographic abnormalities related to neurological outcome after aneurysmal subarachnoid hemorrhage. J Neurosurg 88:28 37, Gruber A, Reinprecht A, Illievich UM, Fitzgerald R, Dietrich W, Czech T, Richling B: Extracerebral organ dysfunction and neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med 27: , Inobe J, Mori T, Ueyama H, Kumamoto T, Tsuda T: Neurogenic pulmonary edema induced by primary medullary hemorrhage. J Neurol Sci 172:73 76, Kassell NF, Torner JC, Haley C Jr, Jane JA, Adams HP, Kongable GL: The International Cooperative Study on the Timing of Aneurysm Surgery: Part 1 Overall management results. J Neurosurg 73:18 36, Kassell NF, Torner JC, Jane JA, Haley C Jr, Adams HP: The International Cooperative Study on the Timing of Aneurysm Surgery: Part 2 Surgical results. J Neurosurg 73:37 47, Keegan MT, Lanier WL: Pulmonary edema after resection of a fourth ventricle tumor: Possible evidence for a medulla-mediated mechanism. Mayo Clin Proc 74: , King WA, Martin NA: Critical care of patients with subarachnoid hemorrhage. 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7 PULMONARY COMPLICATIONS OF ANEURYSMAL SUBARACHNOID HEMORRHAGE 21. Schell AR, Shenoy MM, Friedman SA, Patel AR: Pulmonary edema associated with subarachnoid hemorrhage: Evidence for a cardiogenic origin. Arch Intern Med 147: , Simmons RL, Martin AM, Heisterkamp CA, Ducker TB: Respiratory insufficiency in combat casualties: Part II Pulmonary edema following head injury. Ann Surg 170:39 44, Smith WS, Matthay MA: Evidence for a hydrostatic mechanism in human neurogenic pulmonary edema. Chest 111: , Solenski NJ, Haley EC Jr, Kassell NF, Kongable G, Germanson T, Truskowski L, Torner JC: Medical complications of aneurysmal subarachnoid hemorrhage: A report of the Multicenter Cooperative Aneurysm Study. Crit Care Med 23: , Theodore J, Robin ED: Speculations on neurogenic pulmonary edema. Am Rev Respir Dis 113: , Weir BKA: Pulmonary edema following fatal aneurysm rupture. J Neurosurg 49: , Yabumoto M, Kuriyama T, Iwamoto M, Kinoshita T: Neurogenic pulmonary edema associated with ruptured intracranial aneurysm. Neurosurgery 19: , Acknowledgments We are indebted to Stephen D. Weigand, M.S., and Megan S. Maurer, B.S., for assistance with statistical analysis and to Mary Soper for expert assistance with manuscript preparation. COMMENTS This useful addition to the literature describes a study of a consecutive series of 305 patients with acute aneurysmal subarachnoid hemorrhage (SAH) who were treated for pulmonary complications at the Mayo Clinic during a 7-year period. Friedman et al. found that almost one-fourth of the patients had some sort of problem, the commonest being either pneumonia (approximately equally divided between nosocomial and aspiration) or pulmonary edema. These patients had a significantly higher incidence of symptomatic vasospasm (most likely related to hypervolemic treatment of same) and poor outcome (related to poor clinical condition at time of admission). The article contains a good discussion about a rare condition that complicates aneurysm rupture: neurogenic pulmonary edema. J. Max Findlay Edmonton, Alberta, Canada The authors report that 66 (22%) of 305 patients admitted to the Mayo Clinic within 7 days of SAH developed pulmonary complications. Their multivariate analysis shows that the incidence of symptomatic vasospasm was greater in patients with pulmonary complications, although overall outcome was not adversely affected by these complications. There are relatively few recent studies of medical complications in patients with aneurysmal SAH. The prevalence of these complications depends on the population of aneurysm patients that is studied. Approximately one-third of the patients in this series were in Hunt and Hess Grade 1, and 63% were alert. In comparison, in The International Cooperative Study on the Timing of Aneurysm Surgery (8), only 49% of patients were alert at the time of admission. In that study, 23% of the patients developed pulmonary edema, which was severe in 6% (13). Medical complications clearly are important in this patient population. Additional data from The International Cooperative Study on the Timing of Aneurysm Surgery noted that 40% of patients had at least one severe, life-threatening medical complication. Almost one-fourth of the deaths in the study were attributed to medical complications, a figure that is similar to the proportion of deaths attributed to the direct effects of the initial hemorrhage (19%), rebleeding (22%), and vasospasm (23%). Pulmonary complications were the most common nonneurological cause of death. Friedman et al. also performed multivariate analyses to assess the effect of pulmonary complications on outcome and symptomatic vasospasm. The results of such analyses depend on many factors, including the size of the sample analyzed, the relative prognostic importance of the factors identified or not identified, the factors that are entered into the analysis, and the distribution of the factor in the population studied. The authors noted that pulmonary complications were independently associated with symptomatic vasospasm but not with overall outcome. Previous studies have not identified an association of symptomatic vasospasm with pulmonary complications, although they have included medical or pulmonary complications in the analysis (1, 3 7, 9 12). Similarly, with regard to outcome, previous studies generally have not entered medical or pulmonary complications into their analyses as possible independent variables (2, 8, 14, 15). The preoperative medical condition of the patient has been an important independent prognostic factor in some studies (14), but additional analyses such as the one published here need to be performed to determine the effects of postadmission medical complications. R. Loch Macdonald Chicago, Illinois 1. Adams HP Jr, Kassell NF, Torner JC, Haley EC Jr: Predicting cerebral ischemia after aneurysmal subarachnoid hemorrhage: Influences of clinical condition, CT results, and antifibrinolytic therapy A report of the Cooperative Aneurysm Study. Neurology 37: , Artiola i Fortuny L, Prieto-Valiente L: Long-term prognosis in surgically treated intracranial aneurysms: Part 1 Mortality. J Neurosurg 54:26 34, Brouwers PJ, Dippel DW, Vermeulen M, Lindsay KW, Hasan D, van Gijn J: Amount of blood on computed tomography as an independent predictor after aneurysm rupture. Stroke 24: , Charpentier C, Audibert G, Guillemin F, Civit T, Ducrocq X, Bracard S, Hepner H, Picard L, Laxenaire MC: Multivariate analysis of predictors of cerebral vasospasm occurrence after aneurysmal subarachnoid hemorrhage. Stroke 30: , Claassen J, Bernardini GL, Kreiter K, Bates J, Du YE, Copeland D, Connolly ES, Mayer SA: Effect of cisternal and ventricular blood on risk of delayed cerebral ischemia after subarachnoid hemorrhage: The Fisher scale revisited. Stroke 32: , Hijdra A, van Gijn J, Nagelkerke NJ, Vermeulen M, van Crevel H: Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage. Stroke 19: , Hop JW, Rinkel GJ, Algra A, van Gijn J: Initial loss of consciousness and risk of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Stroke 30: , NEUROSURGERY VOLUME 52 NUMBER 5 MAY

8 FRIEDMAN ET AL. 8. Kassell NF, Torner JC, Haley EC Jr, Jane JA, Adams HP, Kongable GL: The International Cooperative Study on the Timing of Aneurysm Surgery: Part 1 Overall management results. J Neurosurg 73:18 36, Lasner TM, Weil RJ, Riina HA, King JT Jr, Zager EL, Raps EC, Flamm ES: Cigarette smoking-induced increase in the risk of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage. J Neurosurg 87: , Ohman J, Servo A, Heiskanen O: Risks factors for cerebral infarction in good-grade patients after aneurysmal subarachnoid hemorrhage and surgery: A prospective study. J Neurosurg 74:14 20, Qureshi AI, Sung GY, Razumovsky AY, Lane K, Straw RN, Ulatowski JA: Early identification of patients at risk for symptomatic vasospasm after aneurysmal subarachnoid hemorrhage. Crit Care Med 28: , Rabb CH, Tang G, Chin LS, Giannotta SL: A statistical analysis of factors related to symptomatic cerebral vasospasm. Acta Neurochir (Wien) 127:27 31, Solenski NJ, Haley EC Jr, Kassell NF, Kongable G, Germanson T, Truskowski L, Torner JC: Medical complications of aneurysmal subarachnoid hemorrhage: A report of the multicenter, cooperative aneurysm study Participants of the Multicenter Cooperative Aneurysm Study. Crit Care Med 23: , Torner JC, Kassell NF, Wallace RB, Adams HP Jr: Preoperative prognostic factors for rebleeding and survival in aneurysm patients receiving antifibrinolytic therapy: Report of the Cooperative Aneurysm Study. Neurosurgery 9: , Weir B, Rothberg C, Grace M, Davis F: Relative prognostic significance of vasospasm following subarachnoid hemorrhage. Can J Neurol Sci 2: , The Mayo group has reviewed a consecutive series of 305 patients with aneurysmal SAH to examine pulmonary complications and their impact on outcome. They found that the incidence of symptomatic vasospasm was greater in patients with pulmonary complications (63 versus 31%) and that clinical outcomes were worse in patients who were older in a worse clinical grade. The authors suggest that pulmonary complications, aside from their inherent dangers, prevent aggressive management of vasospasm with aggressive hypervolemic, hyperdynamic therapy, specifically limiting fluid administration and liberalizing the use of diuretic agents to optimize pulmonary oxygenation. Although no data have been produced to support this conclusion, the implication is important: the management of vasospasm in patients with pulmonary complications needs to be especially aggressive and ought to rely heavily on early and extensive angioplasty. Hypothetically, angioplasty reduces the need for hypervolemia and its deleterious pulmonary side effects, but these implications remain to be proved. Unfortunately, many of the underlying causes of pulmonary complications (i.e., aspiration at ictus, inability to protect the airway, prolonged intubation, and preexisting cardiac disease) relate to patients presenting conditions and cannot be rectified. In these settings, it is clear that delivery of advanced pulmonary care with the involvement of critical care specialists is essential. Michael T. Lawton San Francisco, California Modigliani and Paul Guillaume with Madame Archipenko on La Croisette at Nice during the winter of (courtesy of Archives Jean Bouret Paul Guillaume).