Distributions of the AUT measure among matched stroke cases and among matched controls were similar (Figure 3). Hypotension (ie, any MAP < 70 mm Hg) was observed in 77 of 104 (74%) stroke cases and 310 of 398 (78%) controls. Median (first quartile, third quartile) AUT values for hypotensive cases and controls were 19 (4, 55) mm Hg-minutes and 19 (6, 48) mm Hg-minutes, respectively.
Based on our zero-inflated negative binomial model, we found no associations between stroke and intraoperative hypotension as measured by AUT. The odds ratio (95% confidence interval) for any positive area (ie, any MAP < 70 mm Hg) comparing stroke cases with controls was estimated at 0.49 (0.18–1.38), which was not statistically significant (P = .18, Wald test for regression model coefficients). Among patients experiencing any intraoperative hypotension (MAP < 70 mm Hg), severity of the hypotension did not differ significantly in patients who did and did not have perioperative strokes (ratio of geometric means [95% confidence interval] of 1.07 [0.76–1.53]; P = .69).
Sensitivity analyses were performed using threshold MAP values of 65 and 60 mm Hg to define the upper bound of our AUT hypotension measure. These also failed to uncover any statistically significant relationship between intraoperative hypotension and postoperative stroke (Table 3; Supplemental Digital Content 1, Supplemental Figure 1,.
We did not identify any statistically significant or clinically important relationship between intraoperative hypotension and perioperative stroke. This differs from a previous study by Bijker et al,13 which found that time spent >30% below baseline was associated with an increased risk of postoperative stroke. We note, however, that those investigators also found no relationship between intraoperative hypotension and postoperative stroke when using several different definitions of hypotension including raw systolic blood pressures below thresholds of 100, 90, 80, and 70 mm Hg; MAPs <70, 60, 50, and 40 mm Hg; and decreases in both systolic and mean blood pressure by 10%, 20%, and 40% from baseline.
We elected a priori not to use measures of hypotension defined relative to patient baseline blood pressure. The definition of “baseline” varies among the literature and, depending on the definition used, may affect the degree of intraoperative hypotension recorded.17 The most consistently available baseline blood pressure values—those immediately before induction and at preoperative clinic visits—may be affected by factors such as perioperative medications, anxiety or white coat hypertension, and acute disease-related suffering; as such, they may poorly reflect patients’ true baseline blood pressure levels. Rather than incorporating these variable and potentially unreliable baseline levels into our measure of hypotension, we accept the limitation that substantial interindividual differences in baseline blood pressure may decrease our ability to detect a relationship between hypotension and postoperative stroke.
Our study differs from Bijker et al17 in not only matching patients and controls by age and type of surgery but also in the same principal procedure. By using propensity scores, which incorporate patient comorbidities, we were able to tightly match patients who did and did not experience perioperative strokes. We also excluded procedures involving the carotid arteries or proximal aorta because they have substantial potential for atheroembolic events. Finally, our study included approximately 3 times as many stroke cases.
At rest, the brain receives approximately 15% of cardiac output and is able to regulate cerebral blood flow across a range of cerebral perfusion pressures (referred to as cerebral autoregulation).18 Traditionally, the range of blood pressures across which cerebral autoregulation is thought to maintain stable blood flow spans approximately 60 to 150 mm Hg. However, recent evidence suggests that the autoregulation range may be smaller and that cerebral blood flow may be more sensitive to hypotension than hypertension.19
Studies of cerebral autoregulation in humans are complicated by the need for pharmacological agents to achieve large perturbations in blood pressure homeostasis—which may affect cerebrovascular autoregulatory mechanisms—and by difficulties in accurate quantification of cerebral blood flow.19,20 Furthermore, autoregulation during hypotension may be compromised by chronic hypertension, increased intracranial pressure, atherosclerosis, and other disease states.21–24 A recent study of cerebral blood flow during cardiopulmonary bypass, for example, reported that the lower limit of autoregulation varied widely between patients and had no relationship with preoperative MAP.25 These factors suggest that determination of a critical lower limit of blood pressure is complicated and highly variable between patients. In our study, we used a measure of hypotension that combined both the severity and the duration of hypotension experienced. In this way, our measure maintains a degree of sensitivity to differences in severity of hypotension between patients even if the threshold under investigation is higher than the “true” critical lower limit of blood pressure.
It remains possible that intraoperative hypotension contributes to perioperative strokes. Indeed, severe and prolonged intraoperative hypotension as a complication of surgery inevitably results in hypoxic damage to end organs, including the brain. A recent study reported that even short durations of hypotension (defined as MAP < 55 mm Hg) during noncardiac surgery were associated with acute kidney injury (AKI) and myocardial injury.26 The relative scarcity of perioperative strokes (compared with postoperative AKI or myocardial infarction) and small number of patients in our sample experiencing severe degrees of intraoperative hypotension preclude the use of this threshold in our analysis. Our sensitivity analyses failed to find any relationship between hypotension and stroke at more severe degrees of hypotension (<65 and <60 mm Hg). Our results suggest that within the typical range of intraoperative blood pressures experienced at our institution, factors other than hypotension contribute more.
We also defined postoperative stroke as occurring up to 30 days after surgery. Although severe hypotensive events or surgical complications may result in strokes that manifest immediately after surgery, the majority of strokes occur between 1 day and 1 week postoperatively, and we sought to include these in our investigation. Any proposed pathological mechanism connecting intraoperative hypotension and postoperative stroke becomes more tenuous with an increasing number of postoperative days; we thus also conducted analyses restricted to strokes only occurring within 3 and 9 postoperative days. There was no substantial change in the results (Supplemental Digital Content 3, Supplemental Table 1, http://links.lww.com/AA/B487). Postoperative hypotension may be a greater contributor to later-occurring strokes than intraoperative hypotension. Postoperative blood pressure measurement is comparatively infrequent and, during the routine assessment of vital signs, patients are often stimulated, which might mask ongoing hypotensive events. The incidence of postoperative hypotension remains poorly characterized and is the subject of current investigation.
We are also limited by our definition of hypotension as <70 mm Hg and our power to detect an association at progressively greater degrees of intraoperative hypotension. A threshold of 70 mm Hg likely represents normal cerebral perfusion for a supine patient; yet, as demonstrated in Figure 4, a substantial proportion of our patients did not experience any hypotension even under this threshold. Because our measure of hypotension includes both depth and length of exposure, this renders it somewhat resilient to the choice of threshold (ie, patients with more severe hypotension will have greater exposure in the model under any chosen threshold regardless of how high); however, the relative scarcity of stroke and further reduction in the number of exposed patients under the threshold decrease our power.
We also conducted sensitivity analyses at lower thresholds for hypotension, but for these analyses the number of exposed patients—and, therefore, our power—is reduced even further (Supplemental Digital Content 1, Supplemental Figure 1, http://links.lww.com/AA/B485; and Supplemental Digital Content 2, Supplement Figure 2, http://links.lww.com/AA/B486). It may be that we are underpowered to detect an association for this rare event using any of our thresholds. Nonetheless, our sample of over 100 postoperative strokes is the largest ever studied in this population.
Our study incorporated an observational, case-control design; it is thus possible that our results might be influenced by confounding variables unavailable in our registry. However, a randomized trial of intraoperative hypotension and postoperative stroke would be ethically challenging.
In summary, we did not find evidence of a relationship between intraoperative hypotension <70 mm Hg and postoperative stroke in adults having nonneurological, noncardiac, and noncarotid surgeries. It thus seems likely that factors other than blood pressure contribute more to the risk of postoperative stroke.
Name: Jason K. Hsieh, BS.
Contribution: This author helped design the study, collect the data, participate in data analysis, and prepare the manuscript.
Name: Jarrod E. Dalton, PhD.
Contribution: This author helped to design the study, participated in data collection, and performed the data analysis.
Name: Dongsheng Yang, MS.
Contribution: This author helped design the study and participate in data collection.
Name: Ehab S. Farag, MD.
Contribution: This author helped design the study.
Name: Daniel I. Sessler, MD.
Contribution: This author helped design the study and prepare the manuscript.
Name: Andrea M. Kurz, MD.
Contribution: This author helped design the study and prepare the manuscript.
This manuscript was handled by: Gregory Crosby, MD.
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