Cerebral autoregulation in cardiopulmonary bypass surgery: a systematic review

Cerebral autoregulation in cardiopulmonary bypass surgery: a systematic review Abstract Cardiopulmonary bypass surgery is associated with a high incidence of neurological complications, including stroke, delirium and cognitive impairment. The development of strategies to reduce the incidence of such neurological events has been hampered by the lack of a clear understanding of their pathophysiology. Cerebral autoregulation (CA), which describes the ability of the brain to maintain a stable cerebral blood flow over a wide range of cerebral perfusion pressures despite changes in blood pressure, is known to be impaired in various neurological disorders. Therefore, we aimed to systematically review studies reporting indices of CA in cardiopulmonary bypass surgery. Databases such as MEDLINE, Web of Science, Cochrane Database of Systematic Reviews and EMBASE were searched for relevant articles. Titles, abstracts and full texts of articles were scrutinized according to predefined selection criteria. Two independent reviewers undertook the methodological quality screening and data extraction of the included studies. Twenty of 2566 identified studies were relevant. Studies showed marked heterogeneity and weaknesses in key methodological criteria (e.g. population size and discussion of limitations). All but 3 of the 20 studies described impairments of CA with cardiac surgery. Eleven studies investigated clinical outcomes, and 9 of these found a significant relationship between these and impaired CA. There is a general agreement that cardiac surgery is associated with changes in CA and that clinical outcomes appear to be significantly related to impaired CA. Further studies are now needed to determine prognostic significance and to inform future therapeutic strategies. Cardiac surgery, Cerebrovascular circulation, Cerebral blood flow regulation, Heart surgery INTRODUCTION Despite continual advancements in surgical and anaesthetic techniques and improvements in cardiopulmonary bypass (CPB) technology, neurological complications remain one of the major hazards of cardiac surgery. The causes of these complications are still not fully established or understood [1]. However, as the complexity of surgical procedures increases and the population ages, neurological complications including adverse cognitive outcomes are of increasing concern. Indeed, postoperative cognitive impairment is found in as many as 69% of patients undergoing cardiac surgery at the time of hospital discharge [2]. Furthermore, delirium affects up to 70% of high-risk patients, and strokes occur in up to 6% of patients after cardiac surgery [3, 4]. The development of strategies to reduce the incidence of such postoperative neurological complications has been hampered by a lack of clear understanding of their pathophysiology. It was believed that the main mechanism of cerebral injury after cardiac surgery was the use of CPB [5]. However, recent studies have not shown a significant risk reduction with the use of off-pump surgery [6–9]. Another traditionally invoked mechanism of brain injury was that of macro- and microembolization, but few studies have shown a robust correlation between the number of emboli and cognitive outcomes [10–12]. Furthermore, a recently published study did not find significant associations between neurological complications and the presence, size or number of new lesions on magnetic resonance imaging [12]. Several neurological disorders with a significant incidence and considerable impact on quality of life, including stroke, head trauma, carotid artery disease and subarachnoid haemorrhage, involve disturbances of cerebral blood flow (CBF) and its regulatory mechanisms [13–15]. However, the effect of cardiac surgery on cerebral autoregulation (CA) is not known. CA is the ability of the brain to maintain a stable CBF over a wide range of different cerebral perfusion pressures despite changes in blood pressure (BP), typically in the range 60–150 mmHg [16]. Autoregulation is accomplished via a complex interplay of myogenic, chemical, metabolic and neurogenic mechanisms and is affected by various factors including arterial BP, intracranial pressure, arterial partial pressure of carbon dioxide, mental activation and posture. If CA is impaired, changes in BP can lead to cerebral ischaemia or to oedema or microvascular damage due to excessive CBF [17]. Methodologically, it is important to distinguish between static and dynamic CA. The former, and more classical approach, uses steady-state measurements of CBF and BP, usually manipulated through the use of pharmacological agents [14–16, 18]. The latter assesses both the efficacy and the latency of transient changes in CBF [or CBF velocity (CBFV)] following rapid changes in BP [13, 15, 17–21]. Cerebral haemodynamics can be assessed using transcranial Doppler (TCD). The temporal resolution of TCD has allowed the analysis of transient CBFV responses to induced and spontaneous changes in BP [17]. Near-infrared spectroscopy (NIRS), another non-invasive method that measures regional cerebral oxygen saturation, can also be used, as well as other modalities of CBF measurement [22, 23–25]. Nevertheless, the individual results have been difficult to interpret, and the overall effect of CPB on CA is not clear. Therefore, the aim of this systematic review was to report in full the literature that has investigated the effects of CPB on CA to improve understanding of the pathophysiology of neurological complications. MATERIALS AND METHODS Search strategy A literature search in the bibliographic databases MEDLINE, Web of Science, Cochrane Database of Systematic Reviews and EMBASE was undertaken by the first author and an independent researcher (V.H.) using the following search terms: Cardiac surgery OR heart surgery OR heart procedures OR thoracic surgery AND cerebral autoregulation OR cerebral haemodynamics OR cerebral haemodynamics OR cerebrovascular circulation OR cerebral blood flow regulation. Different medical subject headings (MeSH) terms or subcategories available on the search databases were truncated to increase the sensitivity of the search. The references and citation indices of the selected articles were hand-searched for additional relevant articles. Peer-reviewed studies detailing the quantification of CA before, during or after CPB surgery were included. Eligibility was assessed by reading abstracts and, if necessary, whole articles. Inclusion and exclusion criteria All identified references published between June 1967 and August 2016 and featuring adult human subjects were eligible for review. References were excluded if they were case reports, abstracts, dissertations, paediatric or animal studies, studies involving operations other than cardiac surgery with CPB, non-English language articles, studies that did not specify the type of cardiac surgery or studies that did not include a measurement of CBF. Case reports and studies of cardiac procedures such as angioplasty, angiography, valvuloplasty and transcatheter aortic valve implantation were also excluded. Data extraction The following data were extracted: (i) population; (ii) number of patients and controls; (iii) time of measurements; (iv) CA challenges (input); (v) method of data analysis; (vi) autoregulation evaluation method (steady-state versus dynamic autoregulation); (vi) clinical outcome; (viii) main conclusions of the study and (ix) status of CA. Two authors (J.R.C. and V.H.) evaluated the selected studies in terms of quality using a checklist adapted from authors, editors and reviews of meta-analyses of observational studies using 15 relevant items [26, 27]. Statistical analysis Because of significant differences in study methodologies, heterogeneity of the CA indices reported and a uniform lack of control data, meta-analysis could not be performed. Instead, a descriptive systematic review was completed. RESULTS Study selection A total of 2566 citations were identified. After dismissing duplicates, non-relevant topics and studies where CBF was not quantified, 38 abstracts remained (Fig. 1). Eight of these studies were subsequently excluded because CA was described using CBF measurement in isolation, without the quantification of BP. Five further studies were excluded as they similarly reported cerebral oxygen saturation without reporting BP. A further 3 were excluded as they reported carbon dioxide reactivity and not CA. One was excluded because it reported effects of drugs on CA, confounding the effect of CPB. One final study was excluded, because it was a trial registration without results. Hence, 20 publications were eligible for review [22–25, 28–43]. Figure 1: View largeDownload slide Flow diagram of the study selection process. CA: cerebral autoregulation; CBF: cerebral blood flow; CO2: carbon dioxide; ScO2: cerebral oxygen saturation; TAVI: transcatheter aortic valve implantation. Figure 1: View largeDownload slide Flow diagram of the study selection process. CA: cerebral autoregulation; CBF: cerebral blood flow; CO2: carbon dioxide; ScO2: cerebral oxygen saturation; TAVI: transcatheter aortic valve implantation. Study details are summarized in Table 1. The median score on the quality checklist was 11 (range 7–13), reflecting incomplete reporting of key methodological criteria in the majority of studies. Table 1: Characteristics of identified publications examining cerebral autoregulation on cardiac surgery with bypass Study  n  Age  Type of surgery  Index  Baseline  During  After CPB  After surgery  Main results and conclusions  TCD     Ševerdija et al. [33]  37  61 ± 6  CABG      30 mmHg PCO2      During CPB, CA parameters were significantly higher (P < 0.01) during hypocapnia compared with both normocapnia and hypercapnia  ARI    6 ± 1  Coherence    0.90 ± 0.10  Gain    3.4 ± 2.0  Phase    0.6 ± 0.3      40 mmHg PCO2  ARI    5 ± 1  Coherence    0.91 ± 0.09  Gain    2.2 ± 0.9  Phase    0.3 ± 0.2      50 mmHg PCO2  ARI    3 ± 2  Coherence    0.95 ± 0.06  Gain    1.4 ± 0.4  Phase    0.1 ± 0.1     Ševerdija et al. [32]  40  60.1 (55.8–68.6)  CABG  ARI  7.5 (7.0–8.0)  Ht > 28      ARI lower during CPB compared with preoperative values, suggesting impaired intraoperative CA. ARI adversely affected by haemodilution and hypercapnia  6.1 (5.5–6.5) PaCO2 4 kPa  5.6 (4.6–6.2) PaCO2 5.3 kPa  3.3 (2.5–4.2) PaCO2 6.6 kPa  Ht < 28  5.5 (4.1–6.2) PaCO2/4 kPa  4.4 (3.9–5.1) PaCO2 5.3 kPa  2.6 (1.6–3.7) PaCO2 6.6 kPa     Preisman et al. [24]  12  64 (49–78)  CABG  sCA RoR  sCA 76.4 ± 22.6 RoR 0.22 ± 0.04    15 min sCA 80.2 ± 12.4 RoR 0.20 ± 0.09 30 min sCA 73.6 ± 14.3 RoR 0.21 ± 0.10) 45 min sCA 74.4 ± 14.6 RoR 0.23 ± 0.14    CVR reduces after CPB, but static and dynamic CA are preserved     Christiansen et al. [23]  8  63 ± 10.1  CABG  Gain      1.2 (0.94–1.49)    No difference between patients and 10 healthy controls  Phase      0.33 (0.15–0.56)  Coherence      0.86 (0.77–0.91)    TCD + UT-NIRS     Murkin et al. [31]  20  63.5 ± 11.3    CFI CFIx Mx  8.6 ± 2.5  6.6 ± 2.3  9.0 ± 3.4    45% of patients demonstrated impaired CA prior to CPB, 30% of patients demonstrated impairment of CA during CPB and 20% demonstrated impaired CA after CPB. Only 5% of patients had worsening of CA after CPB. Impaired CA defined as Mx or CFIx ≤ 0.35       Hori et al. [38]  64  65 ± 8.8  CABG 32 CABG+ Valve 8 Valve 2 Others* 4  Mx    Mx left      Significant correlation and agreement between index. Average Mx values <0.4, suggesting preserved CA intraoperatively    0.31 ± 0.17    Mx right    0.32 ± 0.17  CFVx    CFVx left    0.33 ± 0.19      CFVx right      0.35 ± 0.19    TCD + NIRS     Ono et al. [37]  10  62 ± 10  CABG  Mx Cox  0.10 ± 0.13  0.42 ±  0.14 7 (70%) patients had abnormal AR  0.31 ± 0.14 4 (40%) patients had abnormal AR  3 patients (30%) had abnormal AR on Day 1 postoperatively (COx)  7 (70%) patients had abnormal CA during CPB Abnormal CA defined as Mx ≥ 0.4/COx ≥ 0.3     Easley et al. [36]  109  65 ± 11  CABG 73 CABG+ Valve 8 Valve 23 Others* 5  Mx          Increasing Mx values (suggestive of worsening CA) over the cours of the CPB (P < 0.0001). Greatest change observed during rewarming     Ono et al. [22]  70  61 ± 12  CABG 33 CABG+ Valve 19 Valve 9 Others* 6  Mx    0.27 ± 0.16       Mx did not impair during CPB, but COx impaired (thresholds for impairment ≥0.4 and ≥0.3, respectively        Cox    0.34 ± 0.21     Brady et al. [30]  60  64 ± 13  CABG 36 CABG+ Valve 19 Valve 9  Mx    0.38 (95% CI 0.34–0.43)      CA was disturbed during CPB. Mx cut-off for disturbed CA 0.3–0.5     Ono et al. [28]  234  Intact AR 66 (52–88) Impaired AR 66 (46–89)  CABG 113 CABG+ Valve 26 Valve 34 Others* 8  Mx    Intact AR       47 (20%) patients demonstrated impaired CA during CPB. Impaired CA defined as Mx ≥0.4. Perioperative stroke was more common in patients with impaired CA      0.27 ± 0.12      Impaired AR       0.52 ± 0.08  Cox    Intact AR       0.24 ± 0.16      Impaired AR       0.37 ± 0.16      Joshi et al. [43]  127  65 ± 11  CABG 76 CABG+ Valve 18 Valve 30 Others* 3  Mx  left  left   left     Mx increased during the rewarming phase of CPB compared with baseline (P = 0.0001). After CPB but before wound closure, Mx was higher than at baseline. All 7 strokes that occurred perioperatively were in patients with impaired CBF autoregulation during CPB rewarming  0.17 ± 0.21  0.40 ± 0.19  0.27 ± 0.20  right   right   right   0.17 ± 0.20  0.39 ± 0.19  0.28 ± 0.21    UT-NIRS     Hori et al. [29]  110  65 ± 8.8  CABG 58 CABG+ Valve 16 Valve 34 Others* 2  CFx  0.33 ± 0.17    0.12 ± 0.10    There was a significant decrease in average CFx in ICU compared with that measured during CPB (P < 0.0001), indicating better preserved average CA after surgery with return of pulsatile flow       Hori et al. [40]  110  65 ± 8.8  CABG 50 CABG+ Valve 11 Valve 32 Others* 6  CFx  Delirium   Delirium   Delirium   Delirium   No significant differences in CFx both before and after CPB. However, impaired CA is associated with delirium on postoperative Day 2  0.27 ± 0.16   0.34 ± 0.16   0.25 ± 0.16  0.09 ± 0.12   No delirium   No delirium   No delirium   No Delirium   0.29 ± 0.16  0.34 ± 0.19  0.29 ± 0.16  0.14 ± 0.08    NIRS     Hori et al. [42]  121  71 ± 8.1  CABG 66 CABG+ Valve 25 Valve 22 Others* 8  Cox     Average MAP     Average MAP 74 ± 7.3 mmHg (P = 0.008)  54% of patients experienced hypotension in ICU based on COx. Patients who had average MAP in the ICU below their OptMAP, determined from COx monitoring during CPB, had significantly higher plasma GFAP levels on postoperative Day 1 compared with patients whose MAP remained above the optimal level in ICU        OptMAP    75 ± 6.5 mmHg      OptMAP      78 ± 12.8 mmHg     Hori et al. [41]  491  66.2 ± 11.3  CABG 277 CABG+ Valve 70 Valve 106 Others* 38  Cox    3.448 < LLA      LLA defined as that decrement of MAP at which Cox increased from <0.3 to >0.3. ULA defined as that incremental increase in MAP at which COx increased from <0.3 to >0.3. Frequency of delirium 4-fold higher in patients whose MAP exceeded ULA, but no different with LLA  ULA    0.422 > ULA     Hori et al. [34]  197  71 ± 8.0  CABG 105 CABG+ Valve 38 Valve 45 Others* 9  COx  0.18 (0.07–0.27)  There was a significant increase in COx      COx value significantly increased from baseline during CPB (P < 0.001)     Ono et al. [25]  450  No MMOM   CABG 262 CABG+ Valve 62 Valve 99 Others* 14  COx    No MMOM      A dysregulated pattern (COx ≥0.3 at all MAPs) was observed in 83 (19%) patients. Duration and magnitude of MAP less than LLA was an independent risk factor for MMOM  66 ± 11  0.27 ± 0.18  MMOM   MMOM  68 ± 11  0.26 ± 0.17     Ono et al. [39]  410  66 ± 11  CABG 217 CABG+ Valve 49 Valve 82  COx    48 patients Cox ≥0.3 at all MAPs      In 48 (11.7%) patients, COx was ≥0.3 at all MAPs, and in 14 patients, no clear autoregulation threshold could be determined. Duration and degree MAP outside the autoregulatory thresholds increased in patients with AKI    133Xe injection     Ti et al. [35]  91  61 ± 69  CABG  Relationship of CBF to MAP and CMRO2          CBF increased in response to increased CRMO2 but did not change in response to changes in MAP signifying preserved CA   59 ± 61  Study  n  Age  Type of surgery  Index  Baseline  During  After CPB  After surgery  Main results and conclusions  TCD     Ševerdija et al. [33]  37  61 ± 6  CABG      30 mmHg PCO2      During CPB, CA parameters were significantly higher (P < 0.01) during hypocapnia compared with both normocapnia and hypercapnia  ARI    6 ± 1  Coherence    0.90 ± 0.10  Gain    3.4 ± 2.0  Phase    0.6 ± 0.3      40 mmHg PCO2  ARI    5 ± 1  Coherence    0.91 ± 0.09  Gain    2.2 ± 0.9  Phase    0.3 ± 0.2      50 mmHg PCO2  ARI    3 ± 2  Coherence    0.95 ± 0.06  Gain    1.4 ± 0.4  Phase    0.1 ± 0.1     Ševerdija et al. [32]  40  60.1 (55.8–68.6)  CABG  ARI  7.5 (7.0–8.0)  Ht > 28      ARI lower during CPB compared with preoperative values, suggesting impaired intraoperative CA. ARI adversely affected by haemodilution and hypercapnia  6.1 (5.5–6.5) PaCO2 4 kPa  5.6 (4.6–6.2) PaCO2 5.3 kPa  3.3 (2.5–4.2) PaCO2 6.6 kPa  Ht < 28  5.5 (4.1–6.2) PaCO2/4 kPa  4.4 (3.9–5.1) PaCO2 5.3 kPa  2.6 (1.6–3.7) PaCO2 6.6 kPa     Preisman et al. [24]  12  64 (49–78)  CABG  sCA RoR  sCA 76.4 ± 22.6 RoR 0.22 ± 0.04    15 min sCA 80.2 ± 12.4 RoR 0.20 ± 0.09 30 min sCA 73.6 ± 14.3 RoR 0.21 ± 0.10) 45 min sCA 74.4 ± 14.6 RoR 0.23 ± 0.14    CVR reduces after CPB, but static and dynamic CA are preserved     Christiansen et al. [23]  8  63 ± 10.1  CABG  Gain      1.2 (0.94–1.49)    No difference between patients and 10 healthy controls  Phase      0.33 (0.15–0.56)  Coherence      0.86 (0.77–0.91)    TCD + UT-NIRS     Murkin et al. [31]  20  63.5 ± 11.3    CFI CFIx Mx  8.6 ± 2.5  6.6 ± 2.3  9.0 ± 3.4    45% of patients demonstrated impaired CA prior to CPB, 30% of patients demonstrated impairment of CA during CPB and 20% demonstrated impaired CA after CPB. Only 5% of patients had worsening of CA after CPB. Impaired CA defined as Mx or CFIx ≤ 0.35       Hori et al. [38]  64  65 ± 8.8  CABG 32 CABG+ Valve 8 Valve 2 Others* 4  Mx    Mx left      Significant correlation and agreement between index. Average Mx values <0.4, suggesting preserved CA intraoperatively    0.31 ± 0.17    Mx right    0.32 ± 0.17  CFVx    CFVx left    0.33 ± 0.19      CFVx right      0.35 ± 0.19    TCD + NIRS     Ono et al. [37]  10  62 ± 10  CABG  Mx Cox  0.10 ± 0.13  0.42 ±  0.14 7 (70%) patients had abnormal AR  0.31 ± 0.14 4 (40%) patients had abnormal AR  3 patients (30%) had abnormal AR on Day 1 postoperatively (COx)  7 (70%) patients had abnormal CA during CPB Abnormal CA defined as Mx ≥ 0.4/COx ≥ 0.3     Easley et al. [36]  109  65 ± 11  CABG 73 CABG+ Valve 8 Valve 23 Others* 5  Mx          Increasing Mx values (suggestive of worsening CA) over the cours of the CPB (P < 0.0001). Greatest change observed during rewarming     Ono et al. [22]  70  61 ± 12  CABG 33 CABG+ Valve 19 Valve 9 Others* 6  Mx    0.27 ± 0.16       Mx did not impair during CPB, but COx impaired (thresholds for impairment ≥0.4 and ≥0.3, respectively        Cox    0.34 ± 0.21     Brady et al. [30]  60  64 ± 13  CABG 36 CABG+ Valve 19 Valve 9  Mx    0.38 (95% CI 0.34–0.43)      CA was disturbed during CPB. Mx cut-off for disturbed CA 0.3–0.5     Ono et al. [28]  234  Intact AR 66 (52–88) Impaired AR 66 (46–89)  CABG 113 CABG+ Valve 26 Valve 34 Others* 8  Mx    Intact AR       47 (20%) patients demonstrated impaired CA during CPB. Impaired CA defined as Mx ≥0.4. Perioperative stroke was more common in patients with impaired CA      0.27 ± 0.12      Impaired AR       0.52 ± 0.08  Cox    Intact AR       0.24 ± 0.16      Impaired AR       0.37 ± 0.16      Joshi et al. [43]  127  65 ± 11  CABG 76 CABG+ Valve 18 Valve 30 Others* 3  Mx  left  left   left     Mx increased during the rewarming phase of CPB compared with baseline (P = 0.0001). After CPB but before wound closure, Mx was higher than at baseline. All 7 strokes that occurred perioperatively were in patients with impaired CBF autoregulation during CPB rewarming  0.17 ± 0.21  0.40 ± 0.19  0.27 ± 0.20  right   right   right   0.17 ± 0.20  0.39 ± 0.19  0.28 ± 0.21    UT-NIRS     Hori et al. [29]  110  65 ± 8.8  CABG 58 CABG+ Valve 16 Valve 34 Others* 2  CFx  0.33 ± 0.17    0.12 ± 0.10    There was a significant decrease in average CFx in ICU compared with that measured during CPB (P < 0.0001), indicating better preserved average CA after surgery with return of pulsatile flow       Hori et al. [40]  110  65 ± 8.8  CABG 50 CABG+ Valve 11 Valve 32 Others* 6  CFx  Delirium   Delirium   Delirium   Delirium   No significant differences in CFx both before and after CPB. However, impaired CA is associated with delirium on postoperative Day 2  0.27 ± 0.16   0.34 ± 0.16   0.25 ± 0.16  0.09 ± 0.12   No delirium   No delirium   No delirium   No Delirium   0.29 ± 0.16  0.34 ± 0.19  0.29 ± 0.16  0.14 ± 0.08    NIRS     Hori et al. [42]  121  71 ± 8.1  CABG 66 CABG+ Valve 25 Valve 22 Others* 8  Cox     Average MAP     Average MAP 74 ± 7.3 mmHg (P = 0.008)  54% of patients experienced hypotension in ICU based on COx. Patients who had average MAP in the ICU below their OptMAP, determined from COx monitoring during CPB, had significantly higher plasma GFAP levels on postoperative Day 1 compared with patients whose MAP remained above the optimal level in ICU        OptMAP    75 ± 6.5 mmHg      OptMAP      78 ± 12.8 mmHg     Hori et al. [41]  491  66.2 ± 11.3  CABG 277 CABG+ Valve 70 Valve 106 Others* 38  Cox    3.448 < LLA      LLA defined as that decrement of MAP at which Cox increased from <0.3 to >0.3. ULA defined as that incremental increase in MAP at which COx increased from <0.3 to >0.3. Frequency of delirium 4-fold higher in patients whose MAP exceeded ULA, but no different with LLA  ULA    0.422 > ULA     Hori et al. [34]  197  71 ± 8.0  CABG 105 CABG+ Valve 38 Valve 45 Others* 9  COx  0.18 (0.07–0.27)  There was a significant increase in COx      COx value significantly increased from baseline during CPB (P < 0.001)     Ono et al. [25]  450  No MMOM   CABG 262 CABG+ Valve 62 Valve 99 Others* 14  COx    No MMOM      A dysregulated pattern (COx ≥0.3 at all MAPs) was observed in 83 (19%) patients. Duration and magnitude of MAP less than LLA was an independent risk factor for MMOM  66 ± 11  0.27 ± 0.18  MMOM   MMOM  68 ± 11  0.26 ± 0.17     Ono et al. [39]  410  66 ± 11  CABG 217 CABG+ Valve 49 Valve 82  COx    48 patients Cox ≥0.3 at all MAPs      In 48 (11.7%) patients, COx was ≥0.3 at all MAPs, and in 14 patients, no clear autoregulation threshold could be determined. Duration and degree MAP outside the autoregulatory thresholds increased in patients with AKI    133Xe injection     Ti et al. [35]  91  61 ± 69  CABG  Relationship of CBF to MAP and CMRO2          CBF increased in response to increased CRMO2 but did not change in response to changes in MAP signifying preserved CA   59 ± 61  Others* indicates aortic root, ascending aneurysm. AKI: acute kidney injury; AR: autoregulation; ARI: autoregulation index; CA: cerebral autoregulation; CABG: coronary artery bypass grafting; CBF: cerebral blood flow; CPB: cardiopulmonary bypass; CFx: correlation flow index; CFIx: cerebral flow index correlation index; CFVx: cerebral flow velocity index; CI: confidence interval; CMRO2: cerebral metabolic rate for oxygen; COx: cerebral oximetry index; CVR: cerebrovascular resistance; GFAP: glial fibrillary acidic protein plasma levels; Ht: haematocrit; ICU: intensive care unit; LLA: lower limit of autoregulation; MAP: mean arterial pressure; MMOM: major morbidity and operative mortality; Mx: mean velocity index; OptMAP: optimal mean arterial pressure; PaCO2: arterial partial pressure of carbon dioxide ; PCO2: partial pressure of carbon dioxide; RoR: rate of dynamic autoregulation recovery; sCA: static cerebral autoregulation; TCD: transcranial Doppler; ULA: upper limit of A1:L32; UT-NIRS: ultrasound-tagged near-infrared spectroscopy. Study characteristics and measurement techniques Study size varied from 8 to 491 patients. Only 2 studies analysed CA at 5 periods: baseline, before CPB, during CPB, after CPB and following surgery (Table 1) [37, 40]. CA was evaluated with various imaging modalities: 4 studies evaluated CA using TCD [23, 24, 32, 33], 5 used NIRS [25, 34, 39, 41, 42], 2 used ultrasound-tagged NIRS [29, 40], 6 used TCD and NIRS, [22, 28, 30, 36, 37, 43], 2 used TCD and ultrasound-tagged NIRS [31, 38] and 133Xe clearance was used in just 1 study [35]. Twelve different indices, detailed in Table 2, were used to report CA in these studies. These are summarized in Fig. 2. Information about clinical course and outcome after the surgery in relation to CA was provided in 11 studies [23–25, 28, 29, 36, 39–43]. Table 2: Indices of static and dynamic CA used by studies of CA in cardiac surgery with CPB Index  Definition  Static/ dynamic  References (20 selected studies)  COx  Correlation coefficient between MAP and rScO2  S  [22, 25, 28, 30, 34, 37, 39, 41, 42]  ARI  Autoregulation index [16]  D  [32, 33]  Coherence  Fraction of CBFV power, linearly explained by MAP at each frequency  D  [23, 33]  Phase  TFA phase lag between CBFV and MAP at each frequency [44]  D  [23, 33]  Gain  TFA amplitude between CBFV and BP at each frequency [44]  D  [23, 33]  CFx  Correlation coefficient between changes in MAP and microcirculatory blood flow by UT-NIRS  Sa  [29, 31, 39, 40]  CFIx  CFVx  Mx  Moving Pearson’s correlation coefficient between CBFV and MAP  Sa  [22, 30, 28, 36, 37, 40, 43]  Metabolism flow autoregulation  Change in CBF at two different values of CMRO2 from hypothermia to normothermia  S  [35]  Pressure flow autoregulation  Change in CBF at two different MAP  S  [35]  sCA  Change of CVRi related to change of CPP during the Trendelenburg manoeuvre  S  [24]  RoR  Ratio of slope of CBFV recovery normalised by BP after thigh cuff release  D  [24]  Index  Definition  Static/ dynamic  References (20 selected studies)  COx  Correlation coefficient between MAP and rScO2  S  [22, 25, 28, 30, 34, 37, 39, 41, 42]  ARI  Autoregulation index [16]  D  [32, 33]  Coherence  Fraction of CBFV power, linearly explained by MAP at each frequency  D  [23, 33]  Phase  TFA phase lag between CBFV and MAP at each frequency [44]  D  [23, 33]  Gain  TFA amplitude between CBFV and BP at each frequency [44]  D  [23, 33]  CFx  Correlation coefficient between changes in MAP and microcirculatory blood flow by UT-NIRS  Sa  [29, 31, 39, 40]  CFIx  CFVx  Mx  Moving Pearson’s correlation coefficient between CBFV and MAP  Sa  [22, 30, 28, 36, 37, 40, 43]  Metabolism flow autoregulation  Change in CBF at two different values of CMRO2 from hypothermia to normothermia  S  [35]  Pressure flow autoregulation  Change in CBF at two different MAP  S  [35]  sCA  Change of CVRi related to change of CPP during the Trendelenburg manoeuvre  S  [24]  RoR  Ratio of slope of CBFV recovery normalised by BP after thigh cuff release  D  [24]  a Does not inform latency of the response. ARI: autoregulation index; BP: blood pressure; CA: cerebral autoregulation; CBF: cerebral blood flow; CBFV: cerebral blood flow velocity; CFx: correlation flow index; CFIx: cerebral flow index correlation index; CFVx: cerebral flow velocity index; CMRO2: cerebral metabolic rate for oxygen; COx: cerebral oximetry index; CPP: cerebral perfusion pressure; CVRi: cerebrovascular resistance index; MAP: mean arterial pressure; Mx: mean velocity index; RoR: rate of dynamic autoregulation recovery; rScO2: regional cerebral oxygen saturation; sCA: static cerebral autoregulation; TFA: transfer function analysis; UT-NIRS: ultrasound-tagged-near-infrared spectroscopy. Figure 2: View largeDownload slide Overview of the linear models and analytical methods used in autoregulation studies in this systematic review. ARI: autoregulation index; BP: blood pressure; CA: cerebral autoregulation; CBFV: cerebral blood flow velocity; CFx: correlation flow index; CFIx: cerebral flow index correlation index; CFVx: cerebral flow velocity index; COx: cerebral oximetry index; Mx: mean velocity index; ScO2: cerebral oxygen saturation; TFA: transfer function analysis; RoR: rate of dynamic autoregulation recovery; TTT: tilt test. Figure 2: View largeDownload slide Overview of the linear models and analytical methods used in autoregulation studies in this systematic review. ARI: autoregulation index; BP: blood pressure; CA: cerebral autoregulation; CBFV: cerebral blood flow velocity; CFx: correlation flow index; CFIx: cerebral flow index correlation index; CFVx: cerebral flow velocity index; COx: cerebral oximetry index; Mx: mean velocity index; ScO2: cerebral oxygen saturation; TFA: transfer function analysis; RoR: rate of dynamic autoregulation recovery; TTT: tilt test. Cerebral autoregulation before cardiac surgery Seven studies assessed CA in patients before surgery [24, 29, 31, 32, 34, 36, 37], and 6 of these also described CA during surgery [29, 31, 32, 34, 36, 37]. All but 2 of the 7 studies analysed CA through static methods [29, 31, 34, 36, 37]. Dynamic CA was reported with autoregulation index [32] and rate of dynamic autoregulation recovery [23] indices. Two studies used ultrasound-tagged NIRS [29, 31] and 2 studies used NIRS [34, 37]. None of these studies concluded that CA was impaired before surgery. Cerebral autoregulation during cardiac surgery All but 2 of the 20 studies reported values of CA during CPB [23, 24]. Nine studies [22, 25, 28, 30, 33, 35, 38, 39, 41] exclusively reported intraoperative CA; no pre- or postoperative measurements were made. Of the 18 studies reporting intraoperative CA, all but 2 [35, 40] described impairments of CA with surgery. However, it should be noted that these impairments were only statistically significant in 7 studies [29, 31–34, 36, 43]. Of the remainder, 2 [22, 38] were validation studies of the utility of NIRS during CPB; their statistical models were therefore used to compare intraoperative TCD measurements with NIRS values, rather than to assess CA changes per se. Nevertheless, they described trends consistent with impaired CA during surgery. Four further studies [30, 37, 41, 42] also described trends to impaired CA, or values outside predetermined CA thresholds, but did not provide statistical confirmation. Three studies [25, 28, 39] reported the percentage of patients who had impaired CA during CPB, with values of 19%, 20% and 11.7%, respectively. One study, which determined CA using both cerebral oximetry index (COx) and mean velocity index (Mx) (Table 2), found CA to be impaired according to COx, but not Mx, thresholds [22]. One study reported that haemodilution and hypercapnia in CPB negatively affected CA [32], and 2 studies reported that the largest change in CA was observed during the rewarming phase of CPB [36, 43]. Cerebral autoregulation after cardiac surgery Nine articles analysed CA after CPB and surgery [23, 24, 29, 31, 36, 37, 40, 42, 43]. However, it should be noted that the majority of postoperative recordings were made immediately after cessation of CPB; only 2 studies made an assessment of CA in the intensive care unit after surgery [29, 40]; 1 at 3 h [29] and 1 at Day 1 [40]. Six studies showed that CA recovered after CPB, and 3 reported impaired CA postoperatively [29, 37, 40]. Of these, 2 [29, 40] simply described values outside the predetermined limits of autoregulation but did not provide statistical confirmation, and 1 [37] reported that 30% of patients had abnormal CA as determined by a Cox ≥0.3. Clinical outcomes and cerebral autoregulation Eleven studies reported clinical outcomes in the context of CA and CPB [23–25, 28, 29, 36, 39–43], although one of these simply stated that no patients suffered from gross neurological deficit after the operation [24]. This study notably reported static and dynamic (rate of dynamic autoregulation recovery) CA in patients undergoing CPB and found no significant changes in both. Studies where clinical outcomes were reported in more detail included major mortality and morbidity (defined as operative death, stroke, renal failure, mechanical lung ventilation >48 h or low cardiac output syndrome, acute kidney injury, stroke, postoperative cognitive decline and delirium). Duration and magnitude of mean arterial pressure (MAP) less than the lower limit of autoregulation was found to be an independent risk factor for major mortality and morbidity [25]. Similarly, patients who had excursions of BP outside CA limits were also more likely to develop acute kidney injury [39]. More specifically, the lower limit of CA was found to be increased in patients who developed acute kidney injury [29]. The relationship of impaired CA and stroke is a little less clear; 1 study reported no statistically significant differences in the autoregulation parameters Mx and COx between patients who suffered stroke [28] and those without neurological injury, whereas 2 [36, 45] studies found a significantly increased risk of perioperative stroke if CA was impaired, as determined by Mx. The single study reporting postoperative cognitive decline found that poorer performance on the Stroop Colour Word Test was associated with a higher gain [23]. Both studies investigating CA and postoperative delirium found significant relationships [40, 41]; the risk of delirium was 4-fold higher in those patients whose MAP exceeded the upper (but not the lower) limit of autoregulation [41], and excursions of BP above the determined optimal MAP were associated with both the incidence and the severity of delirium on postoperative Day 2 [40]. DISCUSSION There is general agreement that cardiac surgery is associated with changes in CA, with 17 of the 20 studies reporting that CA is impaired with CPB. None of these studies concluded that CA was impaired before surgery and the majority of these showed that CA recovered after CPB. All but 2 of these studies assessed CA through a static method. Another key finding is that 9 of the 11 studies investigating clinical outcomes, including stroke, acute kidney injury, delirium and mortality, found a significant relationship between these and impaired CA. Impairment of CA renders the brain less tolerant to both low and high MAP, with increased risks of significant brain oligaemia and hyperaemia, respectively. Multiple studies have shown an association of CA impairment with neurological disorders. Although there is significant variation in the imaging modalities, study protocols, timing of CA measurements and indices used to evaluate CA during CPB surgery, and this review adds to the existing literature on cerebral haemodynamic abnormalities in cardiac surgery and indicates that impaired CA may play an important role in the development of neurological complications after cardiac surgery with CPB. Postoperative brain injury significantly contributes to increased morbidity and mortality and has negative consequences on quality of life and costs [5, 46, 47]. Three of the most commonly encountered neurological deficits are postoperative stroke, delirium and cognitive decline [47]. In our review, only 3 studies investigated the link between impaired CA during CPB and postoperative stroke [28, 36, 45] with conflicting results. However, stroke continues to be one of the most debilitating and devastating complications of cardiac surgery. Although there is some evidence to suggest that the incidence may be decreasing slightly, the overall rate of stroke has remained remarkably constant at between 1% and 3% [48]. Our results indicate that impaired CA following cardiac surgery is associated with a higher incidence of postoperative delirium. Delirium is an acute disorder of awareness and attention that has a fluctuating course common after cardiac surgery and is associated with additional new cognitive decline, postoperative stroke, increased morbidity, length of hospitalization, hospital readmission and mortality [4, 47–49]. Cerebral hyperperfusion due to impaired autoregulation has been suggested as the mechanism for delirium occurring in non-surgical patients with acute hypertensive emergencies [50]. Prevention in high-risk patients, and early detection and treatment of those affected, is therefore important to minimize poor outcomes. Owing partly to the assumption that adverse neurological events were specifically related to the use of extracorporeal CPB, techniques have been developed for performing cardiac surgery without the use of CPB (‘off-pump’ surgery). However, recent large, prospective, randomized studies comparing the rates of adverse neurological outcomes after conventional on-pump surgery with those after off-pump surgery have not shown a significant risk reduction associated with the use of off-pump surgery [6–9]. Although the pathogenesis of adverse neurological events after cardiac surgery is probably multifactorial, there is growing evidence that patient-related risk factors are particularly relevant [51]. Of particular concern, given the potential for increased complications, are older patients with pre-existing cerebral vascular disease. In this review, 6 studies assessed CA in patients before surgery but did not show impaired CA. This is surprising, as it is known that patients undergoing cardiac surgery have a higher prevalence of conditions such as heart failure, diabetes and carotid artery disease, all of which are associated with impaired CA [19, 52]. Understanding the significance of impaired preoperative CA therefore has considerable potential to improve models for the prediction of brain damage after cardiac surgery and warrants further investigation. Limitations There are several limitations to this review. First, and most important, the interpretation of the effect of cardiac surgery on CA is hampered by various methodological issues. The studies included used different imaging modalities and indices to quantify CA. This is reflective of the numerous methods of quantification of CA in use at the current time, each with their own inherent assumptions, caveats and specific experimental models. Importantly, no particular method is currently considered to be the ‘gold standard’, but the available indices of CA have notably been shown to yield largely divergent results for the same data [20] and should thus be scrutinized carefully. Furthermore, definitions and assessments of postoperative complications varied between studies, making direct comparisons difficult. Second, data were missing, or insufficient, in several of the studies making complete reporting difficult. Third, the cut-offs used to define impaired CA varied between studies, and all had been arbitrarily determined. The variation in scores on the quality checklists also indicates incomplete reporting of key methodological criteria in the majority of studies. Nonetheless, despite these limitations, in combination these studies strongly suggest that CA is impaired by CPB surgery. Accordingly, although the pathogenesis of neurological sequelae after CPB surgery is likely to be multifactorial, it appears that impairment of CA may well be a key factor. CONCLUSIONS AND FURTHER WORK Unfortunately, neurological sequelae remain an important complication of cardiac surgery, despite significant advances in operative techniques. Given the implication that CPB surgery is associated with impaired CA, further work is now needed to elucidate the exact underlying mechanisms of impaired CA in CPB surgery and to understand causality between impaired CA and poor neurological outcomes. Such work has the potential to inform strategies to reduce postoperative neurological complications. 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Cerebral autoregulation in cardiopulmonary bypass surgery: a systematic review

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.
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1569-9293
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1569-9285
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10.1093/icvts/ivx357
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Abstract

Abstract Cardiopulmonary bypass surgery is associated with a high incidence of neurological complications, including stroke, delirium and cognitive impairment. The development of strategies to reduce the incidence of such neurological events has been hampered by the lack of a clear understanding of their pathophysiology. Cerebral autoregulation (CA), which describes the ability of the brain to maintain a stable cerebral blood flow over a wide range of cerebral perfusion pressures despite changes in blood pressure, is known to be impaired in various neurological disorders. Therefore, we aimed to systematically review studies reporting indices of CA in cardiopulmonary bypass surgery. Databases such as MEDLINE, Web of Science, Cochrane Database of Systematic Reviews and EMBASE were searched for relevant articles. Titles, abstracts and full texts of articles were scrutinized according to predefined selection criteria. Two independent reviewers undertook the methodological quality screening and data extraction of the included studies. Twenty of 2566 identified studies were relevant. Studies showed marked heterogeneity and weaknesses in key methodological criteria (e.g. population size and discussion of limitations). All but 3 of the 20 studies described impairments of CA with cardiac surgery. Eleven studies investigated clinical outcomes, and 9 of these found a significant relationship between these and impaired CA. There is a general agreement that cardiac surgery is associated with changes in CA and that clinical outcomes appear to be significantly related to impaired CA. Further studies are now needed to determine prognostic significance and to inform future therapeutic strategies. Cardiac surgery, Cerebrovascular circulation, Cerebral blood flow regulation, Heart surgery INTRODUCTION Despite continual advancements in surgical and anaesthetic techniques and improvements in cardiopulmonary bypass (CPB) technology, neurological complications remain one of the major hazards of cardiac surgery. The causes of these complications are still not fully established or understood [1]. However, as the complexity of surgical procedures increases and the population ages, neurological complications including adverse cognitive outcomes are of increasing concern. Indeed, postoperative cognitive impairment is found in as many as 69% of patients undergoing cardiac surgery at the time of hospital discharge [2]. Furthermore, delirium affects up to 70% of high-risk patients, and strokes occur in up to 6% of patients after cardiac surgery [3, 4]. The development of strategies to reduce the incidence of such postoperative neurological complications has been hampered by a lack of clear understanding of their pathophysiology. It was believed that the main mechanism of cerebral injury after cardiac surgery was the use of CPB [5]. However, recent studies have not shown a significant risk reduction with the use of off-pump surgery [6–9]. Another traditionally invoked mechanism of brain injury was that of macro- and microembolization, but few studies have shown a robust correlation between the number of emboli and cognitive outcomes [10–12]. Furthermore, a recently published study did not find significant associations between neurological complications and the presence, size or number of new lesions on magnetic resonance imaging [12]. Several neurological disorders with a significant incidence and considerable impact on quality of life, including stroke, head trauma, carotid artery disease and subarachnoid haemorrhage, involve disturbances of cerebral blood flow (CBF) and its regulatory mechanisms [13–15]. However, the effect of cardiac surgery on cerebral autoregulation (CA) is not known. CA is the ability of the brain to maintain a stable CBF over a wide range of different cerebral perfusion pressures despite changes in blood pressure (BP), typically in the range 60–150 mmHg [16]. Autoregulation is accomplished via a complex interplay of myogenic, chemical, metabolic and neurogenic mechanisms and is affected by various factors including arterial BP, intracranial pressure, arterial partial pressure of carbon dioxide, mental activation and posture. If CA is impaired, changes in BP can lead to cerebral ischaemia or to oedema or microvascular damage due to excessive CBF [17]. Methodologically, it is important to distinguish between static and dynamic CA. The former, and more classical approach, uses steady-state measurements of CBF and BP, usually manipulated through the use of pharmacological agents [14–16, 18]. The latter assesses both the efficacy and the latency of transient changes in CBF [or CBF velocity (CBFV)] following rapid changes in BP [13, 15, 17–21]. Cerebral haemodynamics can be assessed using transcranial Doppler (TCD). The temporal resolution of TCD has allowed the analysis of transient CBFV responses to induced and spontaneous changes in BP [17]. Near-infrared spectroscopy (NIRS), another non-invasive method that measures regional cerebral oxygen saturation, can also be used, as well as other modalities of CBF measurement [22, 23–25]. Nevertheless, the individual results have been difficult to interpret, and the overall effect of CPB on CA is not clear. Therefore, the aim of this systematic review was to report in full the literature that has investigated the effects of CPB on CA to improve understanding of the pathophysiology of neurological complications. MATERIALS AND METHODS Search strategy A literature search in the bibliographic databases MEDLINE, Web of Science, Cochrane Database of Systematic Reviews and EMBASE was undertaken by the first author and an independent researcher (V.H.) using the following search terms: Cardiac surgery OR heart surgery OR heart procedures OR thoracic surgery AND cerebral autoregulation OR cerebral haemodynamics OR cerebral haemodynamics OR cerebrovascular circulation OR cerebral blood flow regulation. Different medical subject headings (MeSH) terms or subcategories available on the search databases were truncated to increase the sensitivity of the search. The references and citation indices of the selected articles were hand-searched for additional relevant articles. Peer-reviewed studies detailing the quantification of CA before, during or after CPB surgery were included. Eligibility was assessed by reading abstracts and, if necessary, whole articles. Inclusion and exclusion criteria All identified references published between June 1967 and August 2016 and featuring adult human subjects were eligible for review. References were excluded if they were case reports, abstracts, dissertations, paediatric or animal studies, studies involving operations other than cardiac surgery with CPB, non-English language articles, studies that did not specify the type of cardiac surgery or studies that did not include a measurement of CBF. Case reports and studies of cardiac procedures such as angioplasty, angiography, valvuloplasty and transcatheter aortic valve implantation were also excluded. Data extraction The following data were extracted: (i) population; (ii) number of patients and controls; (iii) time of measurements; (iv) CA challenges (input); (v) method of data analysis; (vi) autoregulation evaluation method (steady-state versus dynamic autoregulation); (vi) clinical outcome; (viii) main conclusions of the study and (ix) status of CA. Two authors (J.R.C. and V.H.) evaluated the selected studies in terms of quality using a checklist adapted from authors, editors and reviews of meta-analyses of observational studies using 15 relevant items [26, 27]. Statistical analysis Because of significant differences in study methodologies, heterogeneity of the CA indices reported and a uniform lack of control data, meta-analysis could not be performed. Instead, a descriptive systematic review was completed. RESULTS Study selection A total of 2566 citations were identified. After dismissing duplicates, non-relevant topics and studies where CBF was not quantified, 38 abstracts remained (Fig. 1). Eight of these studies were subsequently excluded because CA was described using CBF measurement in isolation, without the quantification of BP. Five further studies were excluded as they similarly reported cerebral oxygen saturation without reporting BP. A further 3 were excluded as they reported carbon dioxide reactivity and not CA. One was excluded because it reported effects of drugs on CA, confounding the effect of CPB. One final study was excluded, because it was a trial registration without results. Hence, 20 publications were eligible for review [22–25, 28–43]. Figure 1: View largeDownload slide Flow diagram of the study selection process. CA: cerebral autoregulation; CBF: cerebral blood flow; CO2: carbon dioxide; ScO2: cerebral oxygen saturation; TAVI: transcatheter aortic valve implantation. Figure 1: View largeDownload slide Flow diagram of the study selection process. CA: cerebral autoregulation; CBF: cerebral blood flow; CO2: carbon dioxide; ScO2: cerebral oxygen saturation; TAVI: transcatheter aortic valve implantation. Study details are summarized in Table 1. The median score on the quality checklist was 11 (range 7–13), reflecting incomplete reporting of key methodological criteria in the majority of studies. Table 1: Characteristics of identified publications examining cerebral autoregulation on cardiac surgery with bypass Study  n  Age  Type of surgery  Index  Baseline  During  After CPB  After surgery  Main results and conclusions  TCD     Ševerdija et al. [33]  37  61 ± 6  CABG      30 mmHg PCO2      During CPB, CA parameters were significantly higher (P < 0.01) during hypocapnia compared with both normocapnia and hypercapnia  ARI    6 ± 1  Coherence    0.90 ± 0.10  Gain    3.4 ± 2.0  Phase    0.6 ± 0.3      40 mmHg PCO2  ARI    5 ± 1  Coherence    0.91 ± 0.09  Gain    2.2 ± 0.9  Phase    0.3 ± 0.2      50 mmHg PCO2  ARI    3 ± 2  Coherence    0.95 ± 0.06  Gain    1.4 ± 0.4  Phase    0.1 ± 0.1     Ševerdija et al. [32]  40  60.1 (55.8–68.6)  CABG  ARI  7.5 (7.0–8.0)  Ht > 28      ARI lower during CPB compared with preoperative values, suggesting impaired intraoperative CA. ARI adversely affected by haemodilution and hypercapnia  6.1 (5.5–6.5) PaCO2 4 kPa  5.6 (4.6–6.2) PaCO2 5.3 kPa  3.3 (2.5–4.2) PaCO2 6.6 kPa  Ht < 28  5.5 (4.1–6.2) PaCO2/4 kPa  4.4 (3.9–5.1) PaCO2 5.3 kPa  2.6 (1.6–3.7) PaCO2 6.6 kPa     Preisman et al. [24]  12  64 (49–78)  CABG  sCA RoR  sCA 76.4 ± 22.6 RoR 0.22 ± 0.04    15 min sCA 80.2 ± 12.4 RoR 0.20 ± 0.09 30 min sCA 73.6 ± 14.3 RoR 0.21 ± 0.10) 45 min sCA 74.4 ± 14.6 RoR 0.23 ± 0.14    CVR reduces after CPB, but static and dynamic CA are preserved     Christiansen et al. [23]  8  63 ± 10.1  CABG  Gain      1.2 (0.94–1.49)    No difference between patients and 10 healthy controls  Phase      0.33 (0.15–0.56)  Coherence      0.86 (0.77–0.91)    TCD + UT-NIRS     Murkin et al. [31]  20  63.5 ± 11.3    CFI CFIx Mx  8.6 ± 2.5  6.6 ± 2.3  9.0 ± 3.4    45% of patients demonstrated impaired CA prior to CPB, 30% of patients demonstrated impairment of CA during CPB and 20% demonstrated impaired CA after CPB. Only 5% of patients had worsening of CA after CPB. Impaired CA defined as Mx or CFIx ≤ 0.35       Hori et al. [38]  64  65 ± 8.8  CABG 32 CABG+ Valve 8 Valve 2 Others* 4  Mx    Mx left      Significant correlation and agreement between index. Average Mx values <0.4, suggesting preserved CA intraoperatively    0.31 ± 0.17    Mx right    0.32 ± 0.17  CFVx    CFVx left    0.33 ± 0.19      CFVx right      0.35 ± 0.19    TCD + NIRS     Ono et al. [37]  10  62 ± 10  CABG  Mx Cox  0.10 ± 0.13  0.42 ±  0.14 7 (70%) patients had abnormal AR  0.31 ± 0.14 4 (40%) patients had abnormal AR  3 patients (30%) had abnormal AR on Day 1 postoperatively (COx)  7 (70%) patients had abnormal CA during CPB Abnormal CA defined as Mx ≥ 0.4/COx ≥ 0.3     Easley et al. [36]  109  65 ± 11  CABG 73 CABG+ Valve 8 Valve 23 Others* 5  Mx          Increasing Mx values (suggestive of worsening CA) over the cours of the CPB (P < 0.0001). Greatest change observed during rewarming     Ono et al. [22]  70  61 ± 12  CABG 33 CABG+ Valve 19 Valve 9 Others* 6  Mx    0.27 ± 0.16       Mx did not impair during CPB, but COx impaired (thresholds for impairment ≥0.4 and ≥0.3, respectively        Cox    0.34 ± 0.21     Brady et al. [30]  60  64 ± 13  CABG 36 CABG+ Valve 19 Valve 9  Mx    0.38 (95% CI 0.34–0.43)      CA was disturbed during CPB. Mx cut-off for disturbed CA 0.3–0.5     Ono et al. [28]  234  Intact AR 66 (52–88) Impaired AR 66 (46–89)  CABG 113 CABG+ Valve 26 Valve 34 Others* 8  Mx    Intact AR       47 (20%) patients demonstrated impaired CA during CPB. Impaired CA defined as Mx ≥0.4. Perioperative stroke was more common in patients with impaired CA      0.27 ± 0.12      Impaired AR       0.52 ± 0.08  Cox    Intact AR       0.24 ± 0.16      Impaired AR       0.37 ± 0.16      Joshi et al. [43]  127  65 ± 11  CABG 76 CABG+ Valve 18 Valve 30 Others* 3  Mx  left  left   left     Mx increased during the rewarming phase of CPB compared with baseline (P = 0.0001). After CPB but before wound closure, Mx was higher than at baseline. All 7 strokes that occurred perioperatively were in patients with impaired CBF autoregulation during CPB rewarming  0.17 ± 0.21  0.40 ± 0.19  0.27 ± 0.20  right   right   right   0.17 ± 0.20  0.39 ± 0.19  0.28 ± 0.21    UT-NIRS     Hori et al. [29]  110  65 ± 8.8  CABG 58 CABG+ Valve 16 Valve 34 Others* 2  CFx  0.33 ± 0.17    0.12 ± 0.10    There was a significant decrease in average CFx in ICU compared with that measured during CPB (P < 0.0001), indicating better preserved average CA after surgery with return of pulsatile flow       Hori et al. [40]  110  65 ± 8.8  CABG 50 CABG+ Valve 11 Valve 32 Others* 6  CFx  Delirium   Delirium   Delirium   Delirium   No significant differences in CFx both before and after CPB. However, impaired CA is associated with delirium on postoperative Day 2  0.27 ± 0.16   0.34 ± 0.16   0.25 ± 0.16  0.09 ± 0.12   No delirium   No delirium   No delirium   No Delirium   0.29 ± 0.16  0.34 ± 0.19  0.29 ± 0.16  0.14 ± 0.08    NIRS     Hori et al. [42]  121  71 ± 8.1  CABG 66 CABG+ Valve 25 Valve 22 Others* 8  Cox     Average MAP     Average MAP 74 ± 7.3 mmHg (P = 0.008)  54% of patients experienced hypotension in ICU based on COx. Patients who had average MAP in the ICU below their OptMAP, determined from COx monitoring during CPB, had significantly higher plasma GFAP levels on postoperative Day 1 compared with patients whose MAP remained above the optimal level in ICU        OptMAP    75 ± 6.5 mmHg      OptMAP      78 ± 12.8 mmHg     Hori et al. [41]  491  66.2 ± 11.3  CABG 277 CABG+ Valve 70 Valve 106 Others* 38  Cox    3.448 < LLA      LLA defined as that decrement of MAP at which Cox increased from <0.3 to >0.3. ULA defined as that incremental increase in MAP at which COx increased from <0.3 to >0.3. Frequency of delirium 4-fold higher in patients whose MAP exceeded ULA, but no different with LLA  ULA    0.422 > ULA     Hori et al. [34]  197  71 ± 8.0  CABG 105 CABG+ Valve 38 Valve 45 Others* 9  COx  0.18 (0.07–0.27)  There was a significant increase in COx      COx value significantly increased from baseline during CPB (P < 0.001)     Ono et al. [25]  450  No MMOM   CABG 262 CABG+ Valve 62 Valve 99 Others* 14  COx    No MMOM      A dysregulated pattern (COx ≥0.3 at all MAPs) was observed in 83 (19%) patients. Duration and magnitude of MAP less than LLA was an independent risk factor for MMOM  66 ± 11  0.27 ± 0.18  MMOM   MMOM  68 ± 11  0.26 ± 0.17     Ono et al. [39]  410  66 ± 11  CABG 217 CABG+ Valve 49 Valve 82  COx    48 patients Cox ≥0.3 at all MAPs      In 48 (11.7%) patients, COx was ≥0.3 at all MAPs, and in 14 patients, no clear autoregulation threshold could be determined. Duration and degree MAP outside the autoregulatory thresholds increased in patients with AKI    133Xe injection     Ti et al. [35]  91  61 ± 69  CABG  Relationship of CBF to MAP and CMRO2          CBF increased in response to increased CRMO2 but did not change in response to changes in MAP signifying preserved CA   59 ± 61  Study  n  Age  Type of surgery  Index  Baseline  During  After CPB  After surgery  Main results and conclusions  TCD     Ševerdija et al. [33]  37  61 ± 6  CABG      30 mmHg PCO2      During CPB, CA parameters were significantly higher (P < 0.01) during hypocapnia compared with both normocapnia and hypercapnia  ARI    6 ± 1  Coherence    0.90 ± 0.10  Gain    3.4 ± 2.0  Phase    0.6 ± 0.3      40 mmHg PCO2  ARI    5 ± 1  Coherence    0.91 ± 0.09  Gain    2.2 ± 0.9  Phase    0.3 ± 0.2      50 mmHg PCO2  ARI    3 ± 2  Coherence    0.95 ± 0.06  Gain    1.4 ± 0.4  Phase    0.1 ± 0.1     Ševerdija et al. [32]  40  60.1 (55.8–68.6)  CABG  ARI  7.5 (7.0–8.0)  Ht > 28      ARI lower during CPB compared with preoperative values, suggesting impaired intraoperative CA. ARI adversely affected by haemodilution and hypercapnia  6.1 (5.5–6.5) PaCO2 4 kPa  5.6 (4.6–6.2) PaCO2 5.3 kPa  3.3 (2.5–4.2) PaCO2 6.6 kPa  Ht < 28  5.5 (4.1–6.2) PaCO2/4 kPa  4.4 (3.9–5.1) PaCO2 5.3 kPa  2.6 (1.6–3.7) PaCO2 6.6 kPa     Preisman et al. [24]  12  64 (49–78)  CABG  sCA RoR  sCA 76.4 ± 22.6 RoR 0.22 ± 0.04    15 min sCA 80.2 ± 12.4 RoR 0.20 ± 0.09 30 min sCA 73.6 ± 14.3 RoR 0.21 ± 0.10) 45 min sCA 74.4 ± 14.6 RoR 0.23 ± 0.14    CVR reduces after CPB, but static and dynamic CA are preserved     Christiansen et al. [23]  8  63 ± 10.1  CABG  Gain      1.2 (0.94–1.49)    No difference between patients and 10 healthy controls  Phase      0.33 (0.15–0.56)  Coherence      0.86 (0.77–0.91)    TCD + UT-NIRS     Murkin et al. [31]  20  63.5 ± 11.3    CFI CFIx Mx  8.6 ± 2.5  6.6 ± 2.3  9.0 ± 3.4    45% of patients demonstrated impaired CA prior to CPB, 30% of patients demonstrated impairment of CA during CPB and 20% demonstrated impaired CA after CPB. Only 5% of patients had worsening of CA after CPB. Impaired CA defined as Mx or CFIx ≤ 0.35       Hori et al. [38]  64  65 ± 8.8  CABG 32 CABG+ Valve 8 Valve 2 Others* 4  Mx    Mx left      Significant correlation and agreement between index. Average Mx values <0.4, suggesting preserved CA intraoperatively    0.31 ± 0.17    Mx right    0.32 ± 0.17  CFVx    CFVx left    0.33 ± 0.19      CFVx right      0.35 ± 0.19    TCD + NIRS     Ono et al. [37]  10  62 ± 10  CABG  Mx Cox  0.10 ± 0.13  0.42 ±  0.14 7 (70%) patients had abnormal AR  0.31 ± 0.14 4 (40%) patients had abnormal AR  3 patients (30%) had abnormal AR on Day 1 postoperatively (COx)  7 (70%) patients had abnormal CA during CPB Abnormal CA defined as Mx ≥ 0.4/COx ≥ 0.3     Easley et al. [36]  109  65 ± 11  CABG 73 CABG+ Valve 8 Valve 23 Others* 5  Mx          Increasing Mx values (suggestive of worsening CA) over the cours of the CPB (P < 0.0001). Greatest change observed during rewarming     Ono et al. [22]  70  61 ± 12  CABG 33 CABG+ Valve 19 Valve 9 Others* 6  Mx    0.27 ± 0.16       Mx did not impair during CPB, but COx impaired (thresholds for impairment ≥0.4 and ≥0.3, respectively        Cox    0.34 ± 0.21     Brady et al. [30]  60  64 ± 13  CABG 36 CABG+ Valve 19 Valve 9  Mx    0.38 (95% CI 0.34–0.43)      CA was disturbed during CPB. Mx cut-off for disturbed CA 0.3–0.5     Ono et al. [28]  234  Intact AR 66 (52–88) Impaired AR 66 (46–89)  CABG 113 CABG+ Valve 26 Valve 34 Others* 8  Mx    Intact AR       47 (20%) patients demonstrated impaired CA during CPB. Impaired CA defined as Mx ≥0.4. Perioperative stroke was more common in patients with impaired CA      0.27 ± 0.12      Impaired AR       0.52 ± 0.08  Cox    Intact AR       0.24 ± 0.16      Impaired AR       0.37 ± 0.16      Joshi et al. [43]  127  65 ± 11  CABG 76 CABG+ Valve 18 Valve 30 Others* 3  Mx  left  left   left     Mx increased during the rewarming phase of CPB compared with baseline (P = 0.0001). After CPB but before wound closure, Mx was higher than at baseline. All 7 strokes that occurred perioperatively were in patients with impaired CBF autoregulation during CPB rewarming  0.17 ± 0.21  0.40 ± 0.19  0.27 ± 0.20  right   right   right   0.17 ± 0.20  0.39 ± 0.19  0.28 ± 0.21    UT-NIRS     Hori et al. [29]  110  65 ± 8.8  CABG 58 CABG+ Valve 16 Valve 34 Others* 2  CFx  0.33 ± 0.17    0.12 ± 0.10    There was a significant decrease in average CFx in ICU compared with that measured during CPB (P < 0.0001), indicating better preserved average CA after surgery with return of pulsatile flow       Hori et al. [40]  110  65 ± 8.8  CABG 50 CABG+ Valve 11 Valve 32 Others* 6  CFx  Delirium   Delirium   Delirium   Delirium   No significant differences in CFx both before and after CPB. However, impaired CA is associated with delirium on postoperative Day 2  0.27 ± 0.16   0.34 ± 0.16   0.25 ± 0.16  0.09 ± 0.12   No delirium   No delirium   No delirium   No Delirium   0.29 ± 0.16  0.34 ± 0.19  0.29 ± 0.16  0.14 ± 0.08    NIRS     Hori et al. [42]  121  71 ± 8.1  CABG 66 CABG+ Valve 25 Valve 22 Others* 8  Cox     Average MAP     Average MAP 74 ± 7.3 mmHg (P = 0.008)  54% of patients experienced hypotension in ICU based on COx. Patients who had average MAP in the ICU below their OptMAP, determined from COx monitoring during CPB, had significantly higher plasma GFAP levels on postoperative Day 1 compared with patients whose MAP remained above the optimal level in ICU        OptMAP    75 ± 6.5 mmHg      OptMAP      78 ± 12.8 mmHg     Hori et al. [41]  491  66.2 ± 11.3  CABG 277 CABG+ Valve 70 Valve 106 Others* 38  Cox    3.448 < LLA      LLA defined as that decrement of MAP at which Cox increased from <0.3 to >0.3. ULA defined as that incremental increase in MAP at which COx increased from <0.3 to >0.3. Frequency of delirium 4-fold higher in patients whose MAP exceeded ULA, but no different with LLA  ULA    0.422 > ULA     Hori et al. [34]  197  71 ± 8.0  CABG 105 CABG+ Valve 38 Valve 45 Others* 9  COx  0.18 (0.07–0.27)  There was a significant increase in COx      COx value significantly increased from baseline during CPB (P < 0.001)     Ono et al. [25]  450  No MMOM   CABG 262 CABG+ Valve 62 Valve 99 Others* 14  COx    No MMOM      A dysregulated pattern (COx ≥0.3 at all MAPs) was observed in 83 (19%) patients. Duration and magnitude of MAP less than LLA was an independent risk factor for MMOM  66 ± 11  0.27 ± 0.18  MMOM   MMOM  68 ± 11  0.26 ± 0.17     Ono et al. [39]  410  66 ± 11  CABG 217 CABG+ Valve 49 Valve 82  COx    48 patients Cox ≥0.3 at all MAPs      In 48 (11.7%) patients, COx was ≥0.3 at all MAPs, and in 14 patients, no clear autoregulation threshold could be determined. Duration and degree MAP outside the autoregulatory thresholds increased in patients with AKI    133Xe injection     Ti et al. [35]  91  61 ± 69  CABG  Relationship of CBF to MAP and CMRO2          CBF increased in response to increased CRMO2 but did not change in response to changes in MAP signifying preserved CA   59 ± 61  Others* indicates aortic root, ascending aneurysm. AKI: acute kidney injury; AR: autoregulation; ARI: autoregulation index; CA: cerebral autoregulation; CABG: coronary artery bypass grafting; CBF: cerebral blood flow; CPB: cardiopulmonary bypass; CFx: correlation flow index; CFIx: cerebral flow index correlation index; CFVx: cerebral flow velocity index; CI: confidence interval; CMRO2: cerebral metabolic rate for oxygen; COx: cerebral oximetry index; CVR: cerebrovascular resistance; GFAP: glial fibrillary acidic protein plasma levels; Ht: haematocrit; ICU: intensive care unit; LLA: lower limit of autoregulation; MAP: mean arterial pressure; MMOM: major morbidity and operative mortality; Mx: mean velocity index; OptMAP: optimal mean arterial pressure; PaCO2: arterial partial pressure of carbon dioxide ; PCO2: partial pressure of carbon dioxide; RoR: rate of dynamic autoregulation recovery; sCA: static cerebral autoregulation; TCD: transcranial Doppler; ULA: upper limit of A1:L32; UT-NIRS: ultrasound-tagged near-infrared spectroscopy. Study characteristics and measurement techniques Study size varied from 8 to 491 patients. Only 2 studies analysed CA at 5 periods: baseline, before CPB, during CPB, after CPB and following surgery (Table 1) [37, 40]. CA was evaluated with various imaging modalities: 4 studies evaluated CA using TCD [23, 24, 32, 33], 5 used NIRS [25, 34, 39, 41, 42], 2 used ultrasound-tagged NIRS [29, 40], 6 used TCD and NIRS, [22, 28, 30, 36, 37, 43], 2 used TCD and ultrasound-tagged NIRS [31, 38] and 133Xe clearance was used in just 1 study [35]. Twelve different indices, detailed in Table 2, were used to report CA in these studies. These are summarized in Fig. 2. Information about clinical course and outcome after the surgery in relation to CA was provided in 11 studies [23–25, 28, 29, 36, 39–43]. Table 2: Indices of static and dynamic CA used by studies of CA in cardiac surgery with CPB Index  Definition  Static/ dynamic  References (20 selected studies)  COx  Correlation coefficient between MAP and rScO2  S  [22, 25, 28, 30, 34, 37, 39, 41, 42]  ARI  Autoregulation index [16]  D  [32, 33]  Coherence  Fraction of CBFV power, linearly explained by MAP at each frequency  D  [23, 33]  Phase  TFA phase lag between CBFV and MAP at each frequency [44]  D  [23, 33]  Gain  TFA amplitude between CBFV and BP at each frequency [44]  D  [23, 33]  CFx  Correlation coefficient between changes in MAP and microcirculatory blood flow by UT-NIRS  Sa  [29, 31, 39, 40]  CFIx  CFVx  Mx  Moving Pearson’s correlation coefficient between CBFV and MAP  Sa  [22, 30, 28, 36, 37, 40, 43]  Metabolism flow autoregulation  Change in CBF at two different values of CMRO2 from hypothermia to normothermia  S  [35]  Pressure flow autoregulation  Change in CBF at two different MAP  S  [35]  sCA  Change of CVRi related to change of CPP during the Trendelenburg manoeuvre  S  [24]  RoR  Ratio of slope of CBFV recovery normalised by BP after thigh cuff release  D  [24]  Index  Definition  Static/ dynamic  References (20 selected studies)  COx  Correlation coefficient between MAP and rScO2  S  [22, 25, 28, 30, 34, 37, 39, 41, 42]  ARI  Autoregulation index [16]  D  [32, 33]  Coherence  Fraction of CBFV power, linearly explained by MAP at each frequency  D  [23, 33]  Phase  TFA phase lag between CBFV and MAP at each frequency [44]  D  [23, 33]  Gain  TFA amplitude between CBFV and BP at each frequency [44]  D  [23, 33]  CFx  Correlation coefficient between changes in MAP and microcirculatory blood flow by UT-NIRS  Sa  [29, 31, 39, 40]  CFIx  CFVx  Mx  Moving Pearson’s correlation coefficient between CBFV and MAP  Sa  [22, 30, 28, 36, 37, 40, 43]  Metabolism flow autoregulation  Change in CBF at two different values of CMRO2 from hypothermia to normothermia  S  [35]  Pressure flow autoregulation  Change in CBF at two different MAP  S  [35]  sCA  Change of CVRi related to change of CPP during the Trendelenburg manoeuvre  S  [24]  RoR  Ratio of slope of CBFV recovery normalised by BP after thigh cuff release  D  [24]  a Does not inform latency of the response. ARI: autoregulation index; BP: blood pressure; CA: cerebral autoregulation; CBF: cerebral blood flow; CBFV: cerebral blood flow velocity; CFx: correlation flow index; CFIx: cerebral flow index correlation index; CFVx: cerebral flow velocity index; CMRO2: cerebral metabolic rate for oxygen; COx: cerebral oximetry index; CPP: cerebral perfusion pressure; CVRi: cerebrovascular resistance index; MAP: mean arterial pressure; Mx: mean velocity index; RoR: rate of dynamic autoregulation recovery; rScO2: regional cerebral oxygen saturation; sCA: static cerebral autoregulation; TFA: transfer function analysis; UT-NIRS: ultrasound-tagged-near-infrared spectroscopy. Figure 2: View largeDownload slide Overview of the linear models and analytical methods used in autoregulation studies in this systematic review. ARI: autoregulation index; BP: blood pressure; CA: cerebral autoregulation; CBFV: cerebral blood flow velocity; CFx: correlation flow index; CFIx: cerebral flow index correlation index; CFVx: cerebral flow velocity index; COx: cerebral oximetry index; Mx: mean velocity index; ScO2: cerebral oxygen saturation; TFA: transfer function analysis; RoR: rate of dynamic autoregulation recovery; TTT: tilt test. Figure 2: View largeDownload slide Overview of the linear models and analytical methods used in autoregulation studies in this systematic review. ARI: autoregulation index; BP: blood pressure; CA: cerebral autoregulation; CBFV: cerebral blood flow velocity; CFx: correlation flow index; CFIx: cerebral flow index correlation index; CFVx: cerebral flow velocity index; COx: cerebral oximetry index; Mx: mean velocity index; ScO2: cerebral oxygen saturation; TFA: transfer function analysis; RoR: rate of dynamic autoregulation recovery; TTT: tilt test. Cerebral autoregulation before cardiac surgery Seven studies assessed CA in patients before surgery [24, 29, 31, 32, 34, 36, 37], and 6 of these also described CA during surgery [29, 31, 32, 34, 36, 37]. All but 2 of the 7 studies analysed CA through static methods [29, 31, 34, 36, 37]. Dynamic CA was reported with autoregulation index [32] and rate of dynamic autoregulation recovery [23] indices. Two studies used ultrasound-tagged NIRS [29, 31] and 2 studies used NIRS [34, 37]. None of these studies concluded that CA was impaired before surgery. Cerebral autoregulation during cardiac surgery All but 2 of the 20 studies reported values of CA during CPB [23, 24]. Nine studies [22, 25, 28, 30, 33, 35, 38, 39, 41] exclusively reported intraoperative CA; no pre- or postoperative measurements were made. Of the 18 studies reporting intraoperative CA, all but 2 [35, 40] described impairments of CA with surgery. However, it should be noted that these impairments were only statistically significant in 7 studies [29, 31–34, 36, 43]. Of the remainder, 2 [22, 38] were validation studies of the utility of NIRS during CPB; their statistical models were therefore used to compare intraoperative TCD measurements with NIRS values, rather than to assess CA changes per se. Nevertheless, they described trends consistent with impaired CA during surgery. Four further studies [30, 37, 41, 42] also described trends to impaired CA, or values outside predetermined CA thresholds, but did not provide statistical confirmation. Three studies [25, 28, 39] reported the percentage of patients who had impaired CA during CPB, with values of 19%, 20% and 11.7%, respectively. One study, which determined CA using both cerebral oximetry index (COx) and mean velocity index (Mx) (Table 2), found CA to be impaired according to COx, but not Mx, thresholds [22]. One study reported that haemodilution and hypercapnia in CPB negatively affected CA [32], and 2 studies reported that the largest change in CA was observed during the rewarming phase of CPB [36, 43]. Cerebral autoregulation after cardiac surgery Nine articles analysed CA after CPB and surgery [23, 24, 29, 31, 36, 37, 40, 42, 43]. However, it should be noted that the majority of postoperative recordings were made immediately after cessation of CPB; only 2 studies made an assessment of CA in the intensive care unit after surgery [29, 40]; 1 at 3 h [29] and 1 at Day 1 [40]. Six studies showed that CA recovered after CPB, and 3 reported impaired CA postoperatively [29, 37, 40]. Of these, 2 [29, 40] simply described values outside the predetermined limits of autoregulation but did not provide statistical confirmation, and 1 [37] reported that 30% of patients had abnormal CA as determined by a Cox ≥0.3. Clinical outcomes and cerebral autoregulation Eleven studies reported clinical outcomes in the context of CA and CPB [23–25, 28, 29, 36, 39–43], although one of these simply stated that no patients suffered from gross neurological deficit after the operation [24]. This study notably reported static and dynamic (rate of dynamic autoregulation recovery) CA in patients undergoing CPB and found no significant changes in both. Studies where clinical outcomes were reported in more detail included major mortality and morbidity (defined as operative death, stroke, renal failure, mechanical lung ventilation >48 h or low cardiac output syndrome, acute kidney injury, stroke, postoperative cognitive decline and delirium). Duration and magnitude of mean arterial pressure (MAP) less than the lower limit of autoregulation was found to be an independent risk factor for major mortality and morbidity [25]. Similarly, patients who had excursions of BP outside CA limits were also more likely to develop acute kidney injury [39]. More specifically, the lower limit of CA was found to be increased in patients who developed acute kidney injury [29]. The relationship of impaired CA and stroke is a little less clear; 1 study reported no statistically significant differences in the autoregulation parameters Mx and COx between patients who suffered stroke [28] and those without neurological injury, whereas 2 [36, 45] studies found a significantly increased risk of perioperative stroke if CA was impaired, as determined by Mx. The single study reporting postoperative cognitive decline found that poorer performance on the Stroop Colour Word Test was associated with a higher gain [23]. Both studies investigating CA and postoperative delirium found significant relationships [40, 41]; the risk of delirium was 4-fold higher in those patients whose MAP exceeded the upper (but not the lower) limit of autoregulation [41], and excursions of BP above the determined optimal MAP were associated with both the incidence and the severity of delirium on postoperative Day 2 [40]. DISCUSSION There is general agreement that cardiac surgery is associated with changes in CA, with 17 of the 20 studies reporting that CA is impaired with CPB. None of these studies concluded that CA was impaired before surgery and the majority of these showed that CA recovered after CPB. All but 2 of these studies assessed CA through a static method. Another key finding is that 9 of the 11 studies investigating clinical outcomes, including stroke, acute kidney injury, delirium and mortality, found a significant relationship between these and impaired CA. Impairment of CA renders the brain less tolerant to both low and high MAP, with increased risks of significant brain oligaemia and hyperaemia, respectively. Multiple studies have shown an association of CA impairment with neurological disorders. Although there is significant variation in the imaging modalities, study protocols, timing of CA measurements and indices used to evaluate CA during CPB surgery, and this review adds to the existing literature on cerebral haemodynamic abnormalities in cardiac surgery and indicates that impaired CA may play an important role in the development of neurological complications after cardiac surgery with CPB. Postoperative brain injury significantly contributes to increased morbidity and mortality and has negative consequences on quality of life and costs [5, 46, 47]. Three of the most commonly encountered neurological deficits are postoperative stroke, delirium and cognitive decline [47]. In our review, only 3 studies investigated the link between impaired CA during CPB and postoperative stroke [28, 36, 45] with conflicting results. However, stroke continues to be one of the most debilitating and devastating complications of cardiac surgery. Although there is some evidence to suggest that the incidence may be decreasing slightly, the overall rate of stroke has remained remarkably constant at between 1% and 3% [48]. Our results indicate that impaired CA following cardiac surgery is associated with a higher incidence of postoperative delirium. Delirium is an acute disorder of awareness and attention that has a fluctuating course common after cardiac surgery and is associated with additional new cognitive decline, postoperative stroke, increased morbidity, length of hospitalization, hospital readmission and mortality [4, 47–49]. Cerebral hyperperfusion due to impaired autoregulation has been suggested as the mechanism for delirium occurring in non-surgical patients with acute hypertensive emergencies [50]. Prevention in high-risk patients, and early detection and treatment of those affected, is therefore important to minimize poor outcomes. Owing partly to the assumption that adverse neurological events were specifically related to the use of extracorporeal CPB, techniques have been developed for performing cardiac surgery without the use of CPB (‘off-pump’ surgery). However, recent large, prospective, randomized studies comparing the rates of adverse neurological outcomes after conventional on-pump surgery with those after off-pump surgery have not shown a significant risk reduction associated with the use of off-pump surgery [6–9]. Although the pathogenesis of adverse neurological events after cardiac surgery is probably multifactorial, there is growing evidence that patient-related risk factors are particularly relevant [51]. Of particular concern, given the potential for increased complications, are older patients with pre-existing cerebral vascular disease. In this review, 6 studies assessed CA in patients before surgery but did not show impaired CA. This is surprising, as it is known that patients undergoing cardiac surgery have a higher prevalence of conditions such as heart failure, diabetes and carotid artery disease, all of which are associated with impaired CA [19, 52]. Understanding the significance of impaired preoperative CA therefore has considerable potential to improve models for the prediction of brain damage after cardiac surgery and warrants further investigation. Limitations There are several limitations to this review. First, and most important, the interpretation of the effect of cardiac surgery on CA is hampered by various methodological issues. The studies included used different imaging modalities and indices to quantify CA. This is reflective of the numerous methods of quantification of CA in use at the current time, each with their own inherent assumptions, caveats and specific experimental models. Importantly, no particular method is currently considered to be the ‘gold standard’, but the available indices of CA have notably been shown to yield largely divergent results for the same data [20] and should thus be scrutinized carefully. Furthermore, definitions and assessments of postoperative complications varied between studies, making direct comparisons difficult. Second, data were missing, or insufficient, in several of the studies making complete reporting difficult. Third, the cut-offs used to define impaired CA varied between studies, and all had been arbitrarily determined. The variation in scores on the quality checklists also indicates incomplete reporting of key methodological criteria in the majority of studies. Nonetheless, despite these limitations, in combination these studies strongly suggest that CA is impaired by CPB surgery. Accordingly, although the pathogenesis of neurological sequelae after CPB surgery is likely to be multifactorial, it appears that impairment of CA may well be a key factor. CONCLUSIONS AND FURTHER WORK Unfortunately, neurological sequelae remain an important complication of cardiac surgery, despite significant advances in operative techniques. Given the implication that CPB surgery is associated with impaired CA, further work is now needed to elucidate the exact underlying mechanisms of impaired CA in CPB surgery and to understand causality between impaired CA and poor neurological outcomes. Such work has the potential to inform strategies to reduce postoperative neurological complications. 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Interactive CardioVascular and Thoracic SurgeryOxford University Press

Published: Mar 1, 2018

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