With the increase in life expectancy observed in the last decades, the number of people aged more than 65 yr requiring general anaesthesia has increased to nearly 30% of the whole surgical population . Elderly patients have reduced thresholds for highly invasive and high-risk surgery [1-3], and suffer complications more frequently than people aged less than 65 yr. This is due to the numerous co-morbidities and reduction in physiologic reserve that accompanies aging , resulting in longer hospitalization on average [1-4].
Even though the primary end-point of most general anaesthetics is represented by the central nervous system (CNS), this organ still remains the leastmonitored during anaesthesia. In the last decade, technological research has expanded the application of near-infrared spectroscopy (NIRS) to allow continuous, non-invasive and bedside monitoring of rSO2 through the scalp and skull , providing information on the occurrence of cerebral desaturation that is as accurate as the use of invasive techniques . This new non-invasive monitoring of cerebral oxygenation has been demonstrated to be clinically useful during open-heart surgery, in patients with head injury, and during carotid endarterectomy [7-9]; while a recent study on rSO2 monitoring during orthotopic liver transplantation demonstrated a close correlation between a decline in rSO2 and the increase of neuron-specific enolase used as an index of hypoxia/ischaemia-related cerebral damage . Furthermore, it has been reported that actively maintaining rSO2 above a safety threshold in patients undergoing coronary artery bypass (CAB) surgery is associated with less complication and shorter hospital stay .
However, little information was available to date in the literature on the occurrence of cerebral desaturation in elderly anaesthetized patients undergoing non-cardiac, non-vascular abdominal surgery. We therefore conducted this prospective, multicentre, observational study to evaluate changes in rSO2 and incidence of intraoperative cerebral desaturation in a cohort of aged patients undergoing major abdominal surgery.
The study was conducted at five University Hospitals after obtaining the approval from each Institutional Ethics Committee, and written informed consent from all patients. Each hospital enrolled 12 patients. Patients older than 65 yr and scheduled for major abdominal, non-vascular surgery under general anaesthesia (with an expected duration ≥ 2 h) were considered for the study. Surgical procedures included gastrectomy, colon resection and liver resection. Patients undergoing laparoscopic procedures, with pre-existing cerebral pathology (such as previous episodes of cerebral ischaemia or stroke), with an ASA ≥ IV, or a baseline Mini Mental State Examination (MMSE) score ≤23, and patients whose follow-up was not probable (not expected to be discharged alive from the hospital or with an expected hospital stay <4 days) were excluded.
Standard monitoring was used throughout the procedure, including heart rate (HR), electrocardiography (Lead II), arterial pressure, pulse oximetry and tympanic temperature. Patients were actively warmed throughout the procedure to maintain intraoperative normothermia using a forced-air warming system (Bair-Hugger, Augustine-Medical, USA). rSO2 was continuously monitored using NIRS (INVOS 4100; Somanetics Inc., Troy, MI, USA). Sensors for cerebral oximetry were placed prior to induction of general anaesthesia bilaterally on the right and left sides of the forehead, and covering the forehead from the midline to the start of parietal region just above the supra-orbital margin according to the manufacturers instructions [5,6,8,11]. Data were continuously recorded at 10-s intervals. Baseline saturation was defined as the average saturation value over a 1-min period beginning approximately 3 min after the sensors were applied.
General anaesthesia was then induced with 2 μg kg−1 intravenous (i.v.) fentanyl and 5 mg kg−1 sodium thiopental. After adequate muscle relaxation was obtained with 0.2 mg kg−1 cisatracurium bromide IV, tracheal intubation was performed and mechanical ventilation started using a 40% oxygen in air mixture (tidal volume 7 mL kg−1; respiratory rate 12 min−1; inspiratory to expiratory time 1: 2; inspiratory pause 10%). Mechanical ventilation was adjusted to maintain an end-tidal CO2 partial pressure ranging between 32 and 36 mmHg. General anaesthesia was maintained with sevoflurane by adjusting the end-tidal concentrations between 1% and 4% in order to maintain HR and mean arterial pressure within ±15% of baseline values. Supplemental i.v. boluses of fentanyl (1μg kg−1) were also administered if required to maintain cardiovascular stability; while muscle relaxation was maintained with 2 mg boluses of cisatracurium bromide at the discretion of the attending anaesthesiologists and according to the surgeon's needs. In case of blood losses exceeding 20% the actual haemoglobin concentration was measured and homologous blood transfused based on routine clinical judgement (Hb concentration<9g dL−1, with hypotension and/or tachycardia).
After discontinuation of the inhalational agent at the end of the procedure the time required to recover spontaneous ventilation, open eyes on verbal command, squeeze the observer's hand, and extubation were recorded. Patients were transferred to the post-anaesthesia care unit and the Aldrete score recorded every 15 min until achieving readiness for discharge (Aldrete score ≥ 9) . In each patient the anaesthetic exposure was also calculated normalizing the end-tidal concentration of sevoflurane using the age-adjusted minimally alveolar concentration (MAC) values of sevoflurane .
Postoperative analgesia consisted of IV ketoprofen (100 mg every 8 h) and a patient-controlled analgesia (PCA) infusion of morphine (1 mg bolus; lockout time: 6 min; maximum dose: 6 mg h−1) for the first 72 h after surgery. Occurrence of any adverse event, including nausea, vomiting or other undesirable side-effects was also recorded.
Cognitive function was assessed using the MMSE test. This test combines high validity and reliability with brevity and ease of application, and suggests decline in cognitive function with repeated tests . The MMSE score was measured the day before surgery and then repeated after 1 week. In each hospital the same physician always performed the MMSE. A decrease in MMSE score ≥ 2 points from baseline was considered as a decline in cognitive function [15,16]. Patients were followed daily until hospital discharge and the occurrence of major respiratory, cardiovascular, surgical or neurological complications requiring any unplanned treatment or added diagnostic examination were recorded. Duration of hospital stay was also recorded.
Data from the cerebral oximeter were analysed using a worksheet calculation macro (Excel 5.0; Microsoft, USA). Cerebral desaturation was considered to occur when rSO2 values decreased to less than 75% of baseline; if baseline rSO2 was lower than 50% the threshold for defining cerebral desaturation was a reduction below 80% of baseline values. The mean and minimum values of rSO2 were then calculated in each patient, as were the area defined by 50% at the top and the rSO2 curve on the bottom when rSO2 values declined below 50% and the area under the curve when rSO2 values declined below 75% of baseline (similar calculation). Statistical analysis was performed using Systat 7.0 (SPSS Inc, Chicago, IL, USA); t-test and U-test were used to compare continuous variables as indicated. Categorical data were analysed using the contingency table analysis and the Fisher's exact test. Correlation and linear regression analysis were also used as indicated. Unless otherwise indicated, results are presented as mean (±SD) or numbers (percentage). A value of P ≤ 0.05 was considered as significant.
A total of 60 patients (35 male and 25 female; ASA II–III; age: 72 ± 5 yr; weight: 68 ± 8 kg; height: 166 ± 7 cm) were prospectively studied at the five participating hospitals (12 patients in each hospital) between January and July 2003. A centre-effect was first excluded before performing complete statistical analysis of the whole population.
Surgery was performed uneventfully in all studied patients and no severe intraoperative complication occurred in any patient. Mean duration of surgical procedure was 173 ± 37 min, and mean anaesthetic exposure was 2.5 ± 0.6 MAC hour.
The MMSE score decreased in the whole population from 28 ± 1 before surgery to 27 ± 2 one week after surgery (P = 0.05). One patient among those developing intraoperative cerebral desaturation was lost at the postoperative follow-up. The mean baseline rSO2 value was 63 ± 8% and there was a large patient-to-patient variability in rSO2. Cerebral desaturation, defined as a reduction of rSO2 values below 75% of baseline (80% in case of baseline rSO2 < 50%), occurred in 16 patients (26%), without differences in the incidence among the five participating hospitals. Table 1 shows the patient characteristics data, rSO2 and MMSE scores. The occurrence of intraoperative cerebral desaturation did not affect the recovery profile from anaesthesia and discharge (Fig. 1). No differences in pulse oximetry were observed at any time between patients developing or not developing intraoperative cerebral desaturation.
A decline in cognitive function (decrease in MMSE score ≥ 2 points one week after surgery as compared to baseline value) was observed in 12 patients (20.3%). Early cognitive decline was observed in 6 patients who did not have intraoperative cerebral desaturation (13.6%) and 6 patients who had intraoperative cerebral desaturation (40%) (P = 0.057). Occurrence of intraoperative cerebral desaturation resulted in an increased likelihood for developing postoperative decline of cognitive function of 4.22 (CI95%: 1.1–16).
Postoperative complications requiring an unplanned treatment are shown in Table 2. One patient who did not have intraoperative cerebral desaturation become confused and disoriented 2 days after surgery, and a brain CT scan was performed. The CT scan was negative, and the patient recovered uneventfully within the following 3 days. The mean duration of hospital stay observed in the whole population was 13 ± 7 days (range: 6–39 days). A significant correlation was found between the duration of hospital stay and baseline rSO2, mean rSO2, minimum rSO2 and area under the curve below 50% (AUC rSO2<50%) (Fig. 2). Patients with intraoperative values of AUCrSO2<50% >10 min% showed a median duration of hospital stay of 14 days (range: 5–41 days) as compared to only 10 days (range: 4–30 days) reported in those patients who had an AUCrSO2<50% <10 min% throughout the procedure (P = 0.0005).
Elderly patients are exposed to an increased incidence of perioperative complications and adverse outcome including postoperative cognitive decline , and direct or indirect effects of general anaesthesia on the brain is potentially related to these complications together with inadequate brain oxygenation [10,18-21]. Nonetheless, we do not routinely monitor brain oxygenation in our anaesthetized patients, and use only indirect indicators of adequate brain perfusion, such as haemodynamic profile and peripheral oxygen saturation.
According to the anatomy of brain vasculature, the application of NIRS sensors to the frontal region can provide information on the balance between oxygen demand and supply to the brain tissues supplied by the anterior and middle cerebral arteries. This monitoring technology has been evaluated in patients undergoing cardiac and vascular surgery, where the risk for intraoperative brain hypoperfusion is very high [7,9,11]; however, little information was available on NIRS monitoring in a population of elderly patients undergoing non-cardiac and non-vascular abdominal surgery. Results of this multicentre, prospective, observational study showed that cerebral desaturation can occur in up to one of every five patients also in a population of relatively healthy, elderly patients, and once it occurs it is associated with a four-fold increase of the likelihood of developing postoperative decline of cognitive function during the first week after surgery.
The choice of the MMSE test to evaluate cognitive function undoubtedly represents the major pitfall of this study, since it is well known that this test is not ideally suited to accurately evaluate declines in mental function, while more specific and sensitive tests evaluating each component of cognitive function have been proposed to evaluate the true mental status of the patient more accurately [17,18,21]. Nonetheless, a reduction in the MMSE score ≥ 2 points from baseline in repeated testing suggests that a decline in cognitive function is occurring [14-16]. In agreement with present findings, Monk and colleagues  evaluated postoperative cognitive dysfunction with more sensitive psychometric tests in patients of different age, and reported that in elderly patients the occurrence of cognitive dysfunctions was associated with a higher incidence of intraoperative desaturation and a longer hospital stay.
Very often elderly patients develop mental confusion and cognitive decline early after surgery, and in a smaller proportion of patients these alterations result in late cognitive dysfunction ; the physio-pathology of these alterations remains unclear, but inadequate oxygenation of the brain could be potentially involved. Evaluating the intraoperative changes in rSO2 during orthotopic liver transplantation with postoperative increases in neuron-specific enolase as index of hypoxia/ischaemia-related cerebral damage, Plachky and colleagues  observed that a decrease in cardiac output alone does not predict neurological damage, while reporting a close correlation between decreased rSO2 readings and increased markers of neurological damage during the anhepatic phase. Accordingly, actively maintaining rSO2 above a critical threshold might potentially reduce the severity of ischaemia-induced brain damage, and this could have the potential for improving postoperative outcome, including a reduction of the incidence of postoperative cognitive decline. Accordingly, prospective, randomized studies on much larger populations of elderly patients should be advocated to evaluate this potential benefit of this simple and non-invasive monitoring.
Several patient-related factors can be involved in the explanation of the association between hospital stay and rSO2-derived parameters, including the general health of studied patients. However, the finding that patients with an area under the curve of rSO2 below 50% larger than 10 min% had a 40% longer duration of hospital stay suggests that adjusting the anaesthesia plan to minimize the incidence and duration of cerebral desaturation could potentially benefit the duration of hospital stay. In fact, similar findings have been already reported in previous investigations in patients undergoing cardiac surgery. Austin and colleagues  reported that active interventions based on a multimodal neurophysiologic monitoring, including EEG, Doppler ultrasonography of middle cerebral artery blood flow velocity and transcranial cerebral oximetry, decreased the incidence of postoperative neurological sequelae in a population of children undergoing cardiac surgery, with marked reduction of hospital stay and costs. While in a prospective, randomized, blinded study, Iglesias and colleagues  evaluated the impact of interventions to improve rSO2 on postoperative outcome after CAB surgery, and reported that monitoring and maintaining rSO2 above 75% of baseline was associated with a decreased length of stay after cardiac surgery.
Importantly, the occurrence of cerebral desaturation was not associated with any difference in pulse oximetry; although the study was not powered to evaluate the effects of pulse oximetry monitoring on patient's outcome, this finding is in agreement with those reported by Pedersen and colleagues , who failed to demonstrate any significant difference in the incidence of perioperative complications and duration of hospital stay by monitoring pulse oximetry perioperatively; and similar results have been reported by Plachky and colleagues  during liver transplantation.
Maintenance of the ‘milieu interieur’ is the anaesthesiologist's domain, and this is based on continuous monitoring of patient's vital signs. However, when considering the effects of anaesthetic agents on the brain, the CNS is still the least monitored organ. Transcranial cerebral oximetry is a user-friendly and non-invasive monitor that reflects the balance between cerebral oxygen supply and consumption in large part of the brain tissues, and results of this prospective cohort study not only demonstrate that cerebral desaturation occurs more frequently than we think also in relatively healthy elderly patients undergoing abdominal surgery, but also that the occurrence of intraoperative cerebral desaturation is somehow associated with the occurrence of postoperative decline in cognitive function and delayed hospital discharge. Further studies are warranted to better evaluate future implications of these findings.
The study was entirely supported by funding of the five hospitals only. Authors thank Tyco healthcare Italy for providing sensors for the study at a special price.
Giorgio Danelli MD, Massimiliano Nuzzi MD, Federico Mentegazzi MD (Azienda Ospedaliera Parma, Parma); Giorgio Torri MD, Professor of Anesthesiology, Carla Martani MD, Emanuela Spreafico MD (Ospedale San Raffaele, Milano); Giovanni Fierro MD, Professor of Anesthesiology, Francesco Pugliese MD (Policlinico Umberto I, Roma); Germano De Cosmo MD, Paola Aceto MD (Policlinico Gemelli, Roma); Giuseppe Servillo MD, Professor of Anesthesiology, Fabrizio Monaco MD (Policlinico Federico II, Napoli).
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1On behalf of the Collaborative Italian Study Group on Anaesthesia in Elderly Patients. All clinicians participants are co-authors (the list of names is included in the Appendix).