The impact of cognitive reserve on delayed neurocognitive recovery after major non-cardiac surgery: an exploratory substudy.

Introduction: Delayed neurocognitive recovery is a common and severe complication after surgery and anesthesia with an adverse impact on daily living, morbidity, and mortality. High cognitive reserve may mitigate the development of delayed neurocognitive recovery, however, supporting data is lacking. We aimed to assess the association between cognitive reserve and delayed neurocognitive recovery in the early postoperative period. Methods: This is a substudy of two prospective observational studies. Adult patients undergoing elective major non-cardiac surgery, who were fluent in German, were eligible for study participation. Patients with any pre-existing central nervous system disorders were excluded. Cognitive reserve was assessed using the Cognitive Reserve Index questionnaire. Delayed neurocognitive recovery was defined as a decline in cognitive function compared with baseline assessments and was evaluated with a battery of neuropsychological tests on the day of hospital admission and between day three post procedure and before hospital discharge. Results: A total of 67 patients with a median age of 67 [IQR: (63-73)] years were included in our analysis. We found delayed neurocognitive recovery in 22.4% of patients. There was a significant association between Cognitive Reserve Index questionnaire total score and the occurrence of delayed neurocognitive recovery in the early postoperative period [OR = 0.938, (95% CI, 0.891; 0.988), p = 0.015]. Conclusion: Higher cognitive reserve in elderly patients undergoing major non-cardiac surgery decreases the risk for subsequent delayed neurocognitive recovery in the early postoperative period.

Impact of Intraoperative Fluctuations of Cardiac Output on Cerebrovascular Autoregulation: An Integrative Secondary Analysis of Individual-level Data.

BACKGROUND: Intraoperative impairment of cerebral autoregulation (CA) has been associated with perioperative neurocognitive disorders. We investigated whether intraoperative fluctuations in cardiac index are associated with changes in CA. METHODS: We conducted an integrative explorative secondary analysis of individual-level data from 2 prospective observational studies including patients scheduled for radical prostatectomy. We assessed cardiac index by pulse contour analysis and CA as the cerebral oxygenation index (COx) based on near-infrared spectroscopy. We analyzed (1) the cross-correlation between cardiac index and COx, (2) the correlation between the time-weighted average (TWA) of the cardiac index below 2.5 L min-1 m-2, and the TWA of COx above 0.3, and (3) the difference in areas between the cardiac index curve and the COx curve among various subgroups. RESULTS: The final analysis included 155 patients. The median cardiac index was 3.16 [IQR: 2.65, 3.72] L min-1 m-2. Median COx was 0.23 [IQR: 0.12, 0.34]. (1) The median cross-correlation between cardiac index and COx was 0.230 [IQR: 0.186, 0.287]. (2) The correlation (Spearman ρ) between TWA of cardiac index below 2.5 L min-1 m-2 and TWA of COx above 0.3 was 0.095 (P=0.239). (3) Areas between the cardiac index curve and the COx curve did not differ significantly among subgroups (<65 vs. ≥65 y, P=0.903; 0 vs. ≥1 cardiovascular risk factors, P=0.518; arterial hypertension vs. none, P=0.822; open vs. robot-assisted radical prostatectomy, P=0.699). CONCLUSIONS: We found no meaningful association between intraoperative fluctuations in cardiac index and CA. However, it is possible that a potential association was masked by the influence of anesthesia on CA.

Oscillatory and aperiodic neuronal activity in working memory following anesthesia.

OBJECTIVE: Anesthesia and surgery are associated with cognitive impairment, particularly memory deficits. So far, electroencephalography markers of perioperative memory function remain scarce. METHODS: We included male patients >60 years scheduled for prostatectomy under general anesthesia. We obtained neuropsychological assessments and a visual match-to-sample working memory task with simultaneous 62-channel scalp electroencephalography 1 day before and 2 to 3 days after surgery. RESULTS: Twenty-six patients completed both pre- and postoperative sessions. Compared with preoperative performance, verbal learning deteriorated after anesthesia (California Verbal Learning Test total recall; t25 = -3.25, p = 0.015, d = -0.902), while visual working memory performance showed a dissociation between match and mismatch accuracy (match*session F1,25 = 3.866, p = 0.060). Better verbal learning was associated with an increase of aperiodic brain activity (total recall r = 0.66, p = 0.029, learning slope r = 0.66, p = 0.015), whereas visual working memory accuracy was tracked by oscillatory theta/alpha (7 - 9 Hz), low beta (14 - 18 Hz) and high beta/gamma (34 - 38 Hz) activity (matches: p < 0.001, mismatches: p = 0.022). CONCLUSIONS: Oscillatory and aperiodic brain activity in scalp electroencephalography track distinct features of perioperative memory function. SIGNIFICANCE: Aperiodic activity provides a potential electroencephalographic biomarker to identify patients at risk for postoperative cognitive impairments.

Intraoperative impaired cerebrovascular autoregulation and delayed neurocognitive recovery after major oncologic surgery: a secondary analysis of pooled data.

Cerebral blood flow is tightly regulated by cerebrovascular autoregulation (CVA), and intraoperative impairment of CVA has been linked with perioperative neurocognitive disorders. We aim to assess whether impairment of CVA during major oncologic surgery is associated with delayed neurocognitive recovery (DNCR) postoperatively. We performed a secondary analysis of prospectively collected data. Patients were included if they had undergone complete pre- and postoperative neuropsychological assessments, continuous intraoperative measurement of CVA, and major oncologic surgery for visceral, urological, or gynecological cancer. Intraoperative CVA was measured using the time-correlation method based on near-infrared-spectroscopy, and DNCR was assessed with a neuropsychological test battery. A decline in cognitive function before hospital discharge compared with a preoperative baseline assessment was defined as DNCR. One hundred ninety-five patients were included in the analysis. The median age of the study population was 65 years (IQR: 60-68); 11 patients (5.6%) were female. Forty-one patients (21.0%) fulfilled the criteria for DNCR in the early postoperative period. We found a significant association between impaired intraoperative CVA and DNCR before hospital discharge (OR = 1.042 [95% CI: 1.005; 1.080], p = 0.028). The type of surgery (radical prostatectomy vs. other major oncologic surgery; OR = 0.269 [95% CI: 0.099; 0.728], p = 0.010) and premedication with midazolam (OR = 3.360 [95% CI: 1.039; 10.870], p = 0.043) were significantly associated with the occurrence of DNCR in the early postoperative period. Intraoperative impairment of CVA is associated with postoperative neurocognitive function early after oncologic surgery. Therefore, intraoperative monitoring of CVA may be a target for neuroprotective interventions. The initial studies were retrospectively registered with primary clinical trial registries recognized by the World Health Organization (ClinicalTrials.gov Identifiers: DRKS00010014, 21.03.2016 and NCT04101006, 24.07.2019).

Acute kidney injury and mild therapeutic hypothermia in patients after cardiopulmonary resuscitation - a post hoc analysis of a prospective observational trial.

BACKGROUND: The aim of this study was to investigate the influence of mild therapeutic hypothermia (MTH) on the incidence of and recovery from acute kidney injury (AKI). METHODS: Patients who had undergone successful cardiopulmonary resuscitation (CPR) were included. Serum creatinine and cystatin C were measured at baseline, daily up to 5 days and at ICU discharge. AKI was defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria. MTH was applied for 24 h targeting a temperature of 33 °C. Neurological outcome was assessed with the Cerebral Performance Categories score at hospital discharge. RESULTS: 126 patients were included in the study; 73 patients (58%) developed AKI. Patients treated with MTH had a significantly lower incidence of AKI as compared to normothermia (NT) (44 vs. 69%; p = 0.004). Patients with less favourable neurological outcomes had a significantly higher rate of AKI, although when treated with MTH the occurrence of AKI was reduced (50 vs. 80%; p = 0.017). Furthermore, MTH treatment was accompanied by significantly lower creatinine levels on day 0-1 and at ICU discharge (day 0: 1.12 (0.90-1.29) vs. 1.29 (1.00-1.52) mg/dl; p = 0.016) and lower cystatin C levels on day 0-3 and at ICU discharge (day 0: 0.88 (0.77-1.10) vs. 1.29 (1.06-2.16) mg/l; p < 0.001). CONCLUSIONS: Mild therapeutic hypothermia seems to have a protective effect against the development of AKI and on renal recovery. This may be less pronounced in patients with a favourable neurological outcome.

Hemofiltration induces generation of leukocyte-derived CD31+/CD41- microvesicles in sepsis.

BACKGROUND: Microvesicles (MV) are extracellular vesicles known to be associated with cellular activation and inflammation. Hemofiltration is an effective blood purification technique for patients with renal failure and possibly also eliminates inflammatory mediators in the setting of sepsis. On the other hand, proinflammatory stimuli are induced by blood contacting the artificial membrane during extracorporeal blood purification. In chronic dialysis patients a systemic increase in MV has been described. The aim of the study was to investigate whether hemofilter passage of blood in continuous veno-venous hemofiltration (CVVH) alters MV composition and levels in critically ill patients with sepsis. METHODS: Pre- and postfilter bloods as well as ultrafiltrate samples from intensive care unit patients with severe sepsis were obtained during CVVH with regional citrate anticoagulation. MV subtypes in blood were analyzed by high-sensitivity flow cytometry. Additionally, tissue factor (TF) levels and MV-associated TF activities as well as MV activities were quantified. All parameters were corrected for hemoconcentration applied during CVVH. RESULTS: Twelve patients were analyzed. A significant increase in presumably mostly leukocyte-derived CD31+/CD41- MV (1.32 (1.09-1.93)-fold [median (25th-75th quartiles)], p = 0.021) was observed post- to prefilter, whereas platelet-derived MV as well as AnnexinV-binding MV were unaltered. Increments of AnnexinV+, CD42b+ and CD31+/CD41- MV post- to prefilter correlated with filtration fraction (FF) (all p < 0.05). Significant reductions in MV activity [0.72 (0.62-0.84)-fold, p = 0.002] and TF level [0.95 (0.87-0.99)-fold, p = 0.0093] were detected postfilter compared to prefilter. No MV activity was measurable in ultrafiltrate samples. CONCLUSIONS: Despite clearing a fraction of small PS-exposing MV CVVH does not eliminate larger MV. Concurrently, CVVH induces the release of CD31+/CD4- MV that indicate leukocyte activation during hemofilter passage in septic patients. Increments of several MV subtypes within the hemofilter correlate with FF, which supports common recommendations to keep FF low. A fraction of TF is being cleared by CVVH via ultrafiltration.

Characterization of Microvesicles in Septic Shock Using High-Sensitivity Flow Cytometry.

PURPOSE: Endothelial pathology is considered to play a key role in septic shock. Since endothelial-derived microvesicles (MV) are elevated in various diseases associated with endothelial pathology, they are considered surrogate markers of the endothelial state. By analyzing the signature of circulating MV with high-sensitivity flow cytometry (hsFC), we wanted to test the hypothesis whether endothelial-derived MV are increased in septic shock. METHODS: MV in blood from healthy volunteers and patients with septic shock treated in a medical intensive care unit were quantified by hsFC, which has an improved detection limit of approximately 0.3 µm. RESULTS: Patients with septic shock (n = 30) showed 3-fold higher levels of CD31+/CD41- MV (58.5 (26.4-101.2) [median (25th-75th percentile)] vs. 19.5 (12.8-25.4) MV/µL; P <0.001) compared with healthy volunteers (n = 18). Absolute counts of CD144+, CD62E+, and CD106+ MV, specific for endothelial-derived MV, were low in all groups. The number of CD31+/CD41- MV correlated significantly with leukocyte count (rs = 0.64; P <0.001). Platelet-derived CD41+ MV were significantly elevated in the group dying within 48 h after inclusion (639.1 (321.3-969.7) vs. 221.5 (119.5-456.9) MV/µL; P = 0.037). Patients dying within 48 h had also significantly higher levels of CD31+/CD41-/AnnexinV- MV (51.9 (24.9-259.8) vs. 18.9 (9.7-31) MV/µL; P = 0.028). CONCLUSIONS: Despite an improved detection limit for MV by using hsFC, counts of endothelial-specific MV are unexpectedly low in patients with septic shock. Increased amounts of CD41+ and CD31+/CD41-/AnnexinV- MV indicate release by activated platelets and possibly leukocytes correlating with unfavorable outcome.

Outcome prediction and temperature dependency of MR-proANP and Copeptin in comatose resuscitated patients.

OBJECTIVE: To evaluate the prognostic potential of serum C-terminal provasopressin (CT-proAVP or Copeptin) and midregional pro-A-type natriuretic peptide (MR-proANP) to predict neurological outcome following resuscitation from cardiac arrest. METHODS: In this prospective observational study, we employed novel ultra sensitive immunoassay technology to examine serial serum samples from 134 cardiac arrest patients. Patients were either allocated to mild therapeutic hypothermia using an endovascular device or normothermia. Serial blood samples were obtained from resuscitated cardiac arrest survivors during their first 7 days in an intensive care unit, and serum Copeptin and MR-proANP were measured. Cerebral function assessments were made using cerebral performance categorization (CPC) at discharge from hospital. Copeptin and MR-proANP data were analyzed using dichotomized CPC scores (1-2 versus 3-5). RESULTS: Sixty-nine patients (51%) had a poor outcome (CPC 3-5) at hospital discharge. MR-proANP and Copeptin peaked on day 1 (i.e. 0-24h) with the medians being 249.3pmol/L and 77.2pmol/L, respectively. In the first 48h maximum levels of MR-proANP and Copeptin showed an AUC in the ROC of 0.743 (95% CI: 0.658-0.828) and 0.677 (95% CI: 0.583-0.771). Binary logistic regression revealed MR-proANP and Copeptin within 48h after ROSC being significantly associated with functional outcome (p<0.05). Copeptin within 48h was also associated with outcome in the hypothermia group (p<0.05). CONCLUSION: Systemic levels of MR-proANP and Copeptin peak early in cardiac arrest patients in the 48h post-resuscitation period. MR-proANP and Copeptin were highly predictive for poor outcome in comatose resuscitated patients.

Repeated premature hemofilter clotting during regional citrate anticoagulation as indicator of heparin induced thrombocytopenia.

PURPOSE: Early clinical signs of heparin induced thrombocytopenia (HIT) are nonspecific and include a sudden drop in the number of platelets as well as formation of arterial and venous thromboses. Regional citrate anticoagulation (RCA) is increasingly used as a very effective modality to prevent filter clotting during renal replacement therapy (RRT). We report the first case where repeated premature filter clotting despite RCA indicated a manifestation of HIT. MATERIALS AND METHODS: A 71-year old woman admitted to the ICU for a compartment syndrome of the leg developed septic shock with acute kidney injury requiring continuous veno-venous hemodialysis (CVVHD). Because of unexpected and repeated premature filter clotting during CVVHD using RCA, HIT was suspected. RESULTS: The diagnosis of HIT was confirmed by the presence of IgG antibodies against heparin and platelet factor (PF) 4 complexes and six points in the 4T score. Discontinuation of heparin administration and initiation of systemic anticoagulation with danaparoid sodium resulted in the normalization of platelet count and hemofilter lifetime. CONCLUSION: RCA does not seem to be sufficient to prevent hemofilter clotting during HIT. Thus, in case of repeated premature filter clotting despite RCA, one should suspect HIT and prompt diagnostic workup as well as a switch to alternative anticoagulation.

Secretoneurin as a marker for hypoxic brain injury after cardiopulmonary resuscitation.

PURPOSE: The neuropeptide secretoneurin (SN) shows widespread distribution in the brain. We evaluated whether SN is elevated after cardiopulmonary resuscitation (CPR) and could serve as a potential new biomarker for hypoxic brain injury after CPR. METHODS: This was a prospective observational clinical study. All patients admitted to a tertiary medical intensive care unit after successful CPR with expected survival of at least 24 h were consecutively enrolled from September 2008 to April 2013. Serum SN and neuron-specific enolase were determined in 24 h intervals starting with the day of CPR for 7 days. Neurological outcome was assessed with the Cerebral Performance Categories Scale (CPC) at hospital discharge. RESULTS: A total of 134 patients were included with 49 % surviving to good neurological outcome (CPC 1-2). SN serum levels peaked within the first 24 h showing on average a sixfold increase above normal. SN levels were significantly higher in patients with poor (CPC 3-5) than in patients with good neurological outcome [0-24 h: 75 (43-111) vs. 38 (23-68) fmol/ml, p < 0.001; 24-48 h: 45 (24-77) vs. 23 (16-39) fmol/ml, p < 0.001]. SN determined within the first 48 h showed a receiver operating characteristic (ROC) area under the curve (AUC) of 0.753 (0.665-0.841). NSE in the first 72 h had a ROC-AUC of 0.881 (0.815-0.946). When combining the two biomarkers an AUC of 0.925 (0.878-0.972) for outcome prediction could be reached. CONCLUSIONS: SN is a promising early biomarker for hypoxic brain injury. Further studies will be required for confirmation of these results.