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Anesth Analg 2004;99:1245-1252
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000132971.00206.4A

GENERAL ARTICLES

Perioperative Plasma Concentrations of Stable Nitric Oxide Products Are Predictive of Cognitive Dysfunction After Laparoscopic Cholecystectomy

G. Iohom, FCARCSI*, S. Szarvas, MD DEEA*, V. Larney, FCARCSI*, J. O’Brien, FCARCSI*, E. Buckley, FCARCSI*, M. Butler, MSc{dagger}, and G. Shorten, PhD*

Departments of *Anaesthesia and Intensive Care Medicine and {dagger}Clinical Biochemistry, Cork University Hospital, Cork, Ireland

Address correspondence and reprint requests to Professor G. Shorten, Department of Anesthesia and Intensive Care Medicine, Cork University Hospital, Cork, Ireland. Address e-mail to shorteng{at}shb.ie


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
In this study our objectives were to determine the incidence of postoperative cognitive dysfunction (POCD) after laparoscopic cholecystectomy under sevoflurane anesthesia in patients aged >40 and <85 yr and to examine the associations between plasma concentrations of i) S-100ß protein and ii) stable nitric oxide (NO) products and POCD in this clinical setting. Neuropsychological tests were performed on 42 ASA physical status I–II patients the day before, and 4 days and 6 wk after surgery. Patient spouses (n = 13) were studied as controls. Cognitive dysfunction was defined as deficit in one or more cognitive domain(s). Serial measurements of serum concentrations of S-100ß protein and plasma concentrations of stable NO products (nitrate/nitrite, NOx) were performed perioperatively. Four days after surgery, new cognitive deficit was present in 16 (40%) patients and in 1 (7%) control subject (P = 0.01). Six weeks postoperatively, new cognitive deficit was present in 21 (53%) patients and 3 (23%) control subjects (P = 0.03). Compared with the "no deficit" group, patients who demonstrated a new cognitive deficit 4 days postoperatively had larger plasma NOx at each perioperative time point (P < 0.05 for each time point). Serum S-100ß protein concentrations were similar in the 2 groups. In conclusion, preoperative (and postoperative) plasma concentrations of stable NO products (but not S-100ß) are associated with early POCD. The former represents a potential biochemical predictor of POCD.

IMPLICATIONS: The results of this prospective observational study suggest that preoperative (and postoperative) plasma concentrations of stable nitric oxide products (but not S-100ß) are associated with early postoperative cognitive dysfunction. The former represents a potential biochemical predictor of postoperative cognitive dysfunction.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Ambulatory surgery accounts for about 60% of the elective procedures performed in the United States (1). In many centers, laparoscopic cholecystectomy is performed on an ambulatory basis. Clinical, psychomotor, and cognitive tests may be used to determine the extent to which a patient has recovered from the residual effects of anesthetics (2). Postoperative cognitive dysfunction (POCD) occurs often and consistently, especially in the elderly (3). It is likely that patients who have been discharged from the hospital have minor degrees of residual anesthetic effects. Such effects have safety implications as patients resume normal activities of daily living.

Currently, reliable assessment of cognitive function requires repeated time-consuming neuropsychological testing. Estimation of brain-specific proteins in blood or cerebrospinal fluid (CSF) has been used for this purpose after cardiac and noncardiac surgery (4,5). S-100ß protein is a stable product derived largely from glial tissue and has been used as a marker of neuronal injury. A significant positive correlation between neuropsychological function and serum concentrations of S-100ß protein was found in patients with traumatic head injury (6,7), stroke (8,9), and after cardiac (10) or noncardiac (5) surgery.

Increased CSF and plasma concentrations of nitrate plus nitrite (NO index, NOx) are associated with head injury severity score (P < 0.00001 and P = 0.005, respectively) (11). More recently, increased perioperative plasma concentrations of NOx were found with cognitive deficit after coronary artery bypass grafting (12).

The objectives of this prospective, observational study were to determine the incidence of POCD after laparoscopic cholecystectomy under sevoflurane anesthesia in patients aged >40 and <85 yr and to evaluate perioperative plasma concentrations of S-100ß protein and stable nitric oxide (NO) products as biomarkers of cognitive dysfunction in this clinical setting.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
With institutional ethical approval, and having obtained written informed patient consent, 42 ASA physical status I or II patients, aged 40–85 yr undergoing inpatient laparoscopic cholecystectomy under general anesthesia were studied. Exclusion criteria were psychiatric or active neurological disease, severe visual or auditory disorders, alcoholism, active renal or liver disease, and concurrent nitroglycerin.

All regular medications were continued preoperatively, except diuretics and salicylates (discontinued on the morning of surgery and 14 days preoperatively, respectively). No preanesthetic medication was administered. All patients were fasting for at least 12 h before surgery. Induction of anesthesia was performed by administering sevoflurane 8% in 100% O2 and maintained using a clinically indicated concentration of sevoflurane in an O2/N2O mixture with a fraction of inspired oxygen of 0.30.

A nonsurgical control group (spouses, suitable in terms of the same inclusion/exclusion criteria applied to patients and having obtained written informed consent from each) was studied to determine the effects of repeated neuropsychological testing (practice effect) (13).

Mood was assessed by the Hospital Anxiety and Depression (HAD) Scale (14). The diagnosis of delirium was based on DSM-III-R criteria and the Mini Mental State Examination.

A battery of cognitive tests, including those recommended by the Statement of Consensus 1995, was administered preoperatively, before discharge (4 days) and 6 wk postoperatively (15). Where available, parallel forms of a test were administered at follow-up. A single trained investigator (GI) performed all cognitive assessments.

Domains of cognitive function assessed and the tests used were as follows:

Verbal memory: Rey Auditory Verbal Learning Test (RAVLT). This is a test of immediate memory.
Attention: Trail-Making Test Parts A (TMT A) and B (TMT B) (Halstead-Reitan Neuropsychological Test Battery). These tests assess speed of visual search, attention, and mental flexibility.
Motor speed: Purdue Pegboard test. This is a timed test of manual dexterity and fine motor coordination.
Executive function/verbal fluency: Controlled Oral Word Association Test is a test used to assess word fluency.
Psychomotor speed: Digit Symbol Substitution Test. This test examines rapid visual-motor responses as well as sustained attention and concentration.

Using the reliable change (RC) methodology outlined by Jacobson and Truax (16), a Reliable Change Index (RCI) was calculated for each neuropsychological measure using the baseline and follow-up data of the control subjects.

First, the test-retest reliability coefficient (rxx) was computed for each measure (Pearson correlation between baseline and subsequent scores), from which the standard error of measurement (SEm) was calculated using the formula SEm = SD ({surd} [1 – rxx]) for each measurement at each testing time, where SD is the respective standard deviation.

The standard error of the difference (SEdiff) score was then computed as follows: SEdiff = {surd} [(SEm1)2 + (SEm2)2], where SEm1 and SEm2 are the standard error of measurement values at each testing, respectively.

The standard error of the difference describes the distribution of changes in scores that would be expected if no true change had occurred.

The SEdiff value is then multiplied by the desired confidence band (i.e., ±1.64, 90% confidence interval) to establish a range of change scores. When an individual change score occurs outside this confidence interval, it is deemed to be an uncommon occurrence within a particular population <10% of the time (i.e., <5% on each end of the change scores distribution. A correction factor also was added to the confidence interval to minimize any bias introduced by practice effects similar to previous studies (17).

The practice effect was calculated for each measure as the mean of the difference between each pair of pre- and postoperative control scores. Thus, an RC 90% confidence interval was calculated from the following formula for each variable:


Formula 1

The resulting threshold values were rounded to the nearest whole number outside the 90% RC interval. For each neuropsychological measure, a postoperative minus preoperative score difference was calculated for each patient. When this score was outside the RC interval, a statistically significant change in performance on that measure was considered to have occurred.

Plasma concentrations of stable NO products were estimated preoperatively (T1), after induction of anesthesia (T2), at the end of surgery before discontinuing sevoflurane (T3), and at 30 min, 2, 4, 12, 24, and 48 h postoperatively (T4–9). NO oxidation products were measured using a Nitric Oxide Chemiluminescent Analyzer, Sievers 280 NOATM (Sievers Instruments, Boulder, CO). In solution, NO reacts with molecular oxygen to form nitrite (NO2–) and with oxyhemoglobin and superoxide anion (O2–) to form nitrate (NO3–). By adding acid and reducing agents, oxides of nitrogen can be measured in liquid samples. To measure nitrate, vanadium (III) chloride in hydrochloric acid is used to convert nitrate to NO.


Formula 2

To measure nitrite, sodium iodide in acetic acid is used to convert nitrite to NO.


Formula 3

An inert gas is then used to purge NO from solution for subsequent detection by chemiluminescence. The detector is based on the reaction of NO with ozone (O3), which produces nitrogen dioxide in an excited state (NO2*) and molecular oxygen. The excited state of NO2* decays to emit an infrared chemiluminescence >600 nm. Light emission is directly related to the NO content of the sample. Sodium nitrate and nitrite were used as standards.


Formula 4



Formula 5

Serum concentrations of S-100ß protein were measured before surgery (T1), at the end of surgery (T2), and at 1, 2, and 4 h postoperatively (T3–5). S-100ß protein was determined using a commercially available monoclonal two-site sandwich immunoluminometric method LIA-mat® Sangtec® 100 (AB Sangtec Medical, Bromma, Sweden). The sensitivity of this method is <0.02 µg/L. The sample is incubated with 125I-labeled monoclonal antibody to S-100ß protein. The concentration of S-100ß protein in the sample is determined by measuring the radioactive count rate against that of calibration standards.

The expected incidence of POCD in middle-aged patients is 19.2% 1 wk and 6.2% 3 mo after noncardiac surgery (18).

Based on {alpha} = 0.05 and ß = 0.2, a minimal sample size of 40 was required to identify a difference of one standard deviation in NOx between the patient (deficit and no deficit) groups. Differences between pre- and postoperative concentrations of S-100ß protein and stable NO products, differences in concentrations between deficit and no deficit groups were compared using repeated measures analysis of variance followed by Bonferroni’s multiple comparison test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Forty-two adult ASA physical status I or II patients undergoing laparoscopic cholecystectomy under sevoflurane anesthesia were enrolled in the study. Two patients were subsequently excluded, because of cancellation of surgery, immediately after recruitment. Thirteen patient spouses were also studied as a control group. Patients and controls were similar in terms of demographics and preoperative cognitive test scores (Table 1). Delirium was not found in any subject at any stage.


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  		Table 1. Demographics, Duration of Anesthesia, and Preoperative Cognitive Test Scores
 
Data obtained from control subjects used to calculate the RCI for the interval from preoperatively to 4 days postoperatively are summarized in Table 2a and those for the interval from preoperatively to 6 wk postoperatively in Table 2b. Each cognitive test showed acceptable test-retest reliability, ranging from 0.68 (TMT A) to 0.93 (RAVLT), except TMT B at 6 wk (0.37) (Table 2a and b).


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  		Table 2. Test-Retest Reliability, Reliable Change (RC) Cut-Off Scores, Correction for Practice Effects, and Corrected RC Intervals for Control Subjects
 
Four days postoperatively, cognitive deficit, defined by deficit in one or more cognitive domains using the RC method, was present in 16 (40%) patients and in 1 (7%) control subject (P = 0.01). Six weeks after surgery, cognitive deficit was present in 21 (53%) patients and 3 (23%) control subjects (P = 0.03). The changes in cognitive function for each measure using the RC method are summarized in Table 3. Eight of the 16 patients with POCD at 4 days continued to have POCD 6 wk postoperatively. Thirteen of 21 patients with POCD at 6 wk presented new cognitive deficit.


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  		Table 3. Changes in Cognitive Function Tests at 4 Days and 6 Wk Postoperatively
 
The HAD scores were similar in patients and controls preoperatively, and 4 days and 6 wk postoperatively. These scores were also similar in patients who did and did not demonstrate new cognitive deficit 4 days and 6 wk postoperatively.

The perioperative profile of NOx plasma concentrations is shown in Figure 1. Patients who demonstrated new cognitive deficit 4 days postoperatively had more NOx preoperatively and at each subsequent postoperative time point compared with those who did not (Fig. 2). The sensitivity, specificity, and positive and negative predictive values of selected thresholds for NOx of i) 22 and ii) 20 µmol/L for new postoperative cognitive deficit at each sampling time are presented in Table 4. Plasma NOx were similar in those who subsequently developed cognitive deficit at 6 wk and those who did not. However, patients who showed a deficit in immediate verbal memory (RAVLT) at 6 wk had larger plasma NOx at 12 h after surgery (18.2 ± 10.3 µmol/L) compared with the nondeficit group (12.6 ± 6.4 µmol/L, P = 0.02) (Fig. 3).


Figure 1
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  		Figure 1. Plasma concentrations of nitric oxide. *P < 0.05 refers to comparisons to preoperative values.

 

Figure 2
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  		Figure 2. Perioperative plasma concentrations of nitric oxide in patients with and without postoperative cognitive dysfunction at 4 days after surgery. *P < 0.05 refers to between groups comparisons.

 

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  		Table 4. Predictive Values of Two Cut-Off Plasma Concentrations of Nitric Oxide (NOx)
 

Figure 3
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  		Figure 3. Perioperative plasma concentrations of nitric oxide in patients with and without Rey Auditory Verbal Learning Test (RAVLT) deficit at 6 wk. *P = 0.02 refers to between groups comparisons.

 
S-100ß protein serum concentrations were larger at the end of surgery, 1 and 2 h postoperatively compared with preoperatively (0.24 ± 0.1, 0.26 ± 0.1, 0.24 ± 0.1 versus 0.21 ± 0.1 µg/L, P < 0.05). S-100ß protein serum concentrations were similar in patients who did, and did not, subsequently develop early or late POCD.

Had we defined POCD as decline in 2 or more domains, a new deficit 4 days after surgery was present in only 3 (7.5%) patients and no spouse (P = 0.17), and at 6 wk after surgery was present in 2 (5%) patients and in 1 (7%) control (P = 0.3). Although this alternative definition would have resulted in identification of a smaller number of patients with a new deficit, a similar association with plasma concentrations of NOx was still demonstrable. Using the latter definition, plasma concentrations of NOx were larger in the deficit (compared with nondeficit) group preoperatively (33.9 ± 28.7 versus 17.9 ± 6.6 µmol/L, P < 0.01), after induction of anesthesia (27.2 ± 18.5 versus 17.4 ± 6.7 µmol/L, P = 0.02), at the end of surgery (27.9 ± 16.4 versus 17.4 ± 6.5 µmol/L, P = 0.01), 30 min (28.9 ± 17.8 versus 16.9 ± 6.4 µmol/L, P < 0.01), and 2 (28.6 ± 12.5 versus 16.6 ± 6.3 µmol/L, P < 0.01) and 4 h after surgery (24.7 ± 11.4 versus 15.5 ± 6.5 µmol/L, P = 0.01) (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The most important finding of this study is that after laparoscopic cholecystectomy, preoperative and subsequent postoperative plasma concentrations of NOx are associated with early POCD.

Our finding of a 40% incidence of new POCD 4 days after laparoscopic cholecystectomy is consistent with other reports after noncardiac surgery (5). The incidence of new POCD observed 6 weeks postoperatively in this study (53%) is more than those previously reported (10% in the elderly and 6.2% in middle-aged patients 3 months after noncardiac surgery) and we do not have a satisfactory explanation for the observed difference (18,19). In previous investigations, important methodological differences are apparent. We selected the neuropsychological tests and end-points based on recommendations arising from the International Study of Postoperative Cognitive Dysfunction (20). We selected as our definition of POCD, deficit in one or more cognitive domains (5,20). Under these circumstances, the detected deficit may be a very subtle one, revealed only by extensive testing. Using the alternative definition of POCD as decline in 2 or more domains, a new deficit would have been present in only 3 (7.5%) patients at 4 days and in 2 (5%) patients 6 weeks after surgery. However, a similar association with plasma concentrations of NOx was still demonstrable.

NO is difficult to measure in vivo because of its short half-life. However, the stable and inactive end products of NO, nitrate (NO3–) and nitrite (NO2–), can be quantified in biological fluids and provide a useful method of indirectly estimating endogenous NO production (21,22).

Plasma concentrations of NOx reported in this study are consistent with those of previous investigations in the perioperative setting. Compared with preoperative values (21.5 ± 2.1 nmol/mL), serum concentrations of NOx were less at the end of surgery (15.5 ± 1.4 nmol/mL, P < 0.05), on postoperative day 1 (13.3 ± 1.4 nmol/mL, P < 0.01) and 3 (11.6 ± 2.0 nmol/mL, P < 0.01) after major upper abdominal and thoracoabdominal surgery (23). In addition, the serum NOx concentration correlated negatively with the plasma lactate levels (r = 0.41, n = 65, P < 0.01), suggestive of tissue hypoperfusion both during and after major surgery as a causative factor (23).

In our study, a decrease in plasma NOx was noted up to 12 hours after surgery, then the values returned to baseline by 24 hours and increased by 48 hours, as patients in our study resumed oral intake on the first postoperative day.

Interestingly, preoperative concentrations of plasma NO products were larger in the deficit compared with the no deficit group. The explanation for such a preoperative difference may be attributed to the severity of the underlying atheromatous disease, likelihood of cerebral microemboli, or coexisting conditions such as hypertension.

The mechanism underlying the differences in perioperative plasma concentrations of NOx in the deficit compared with the no deficit group (Fig. 2) is unclear. Our results are consistent with the well established effect of cerebral ischemia on NO release from the brain. In animal models, acute global ischemia has been shown to up-regulate neuronal NO synthase (nNOS) within minutes (24), and to induce iNOS within hours (25), resulting in a marked increase in NO release and associated NO activity in the brain. The resulting NO activity is an important mediator of the subsequent cerebral injury but may also have a role in the repair process (26). NO promotes neuronal injury by causing oxidative injury, energy depletion, DNA damage, inhibiting DNA synthesis, and triggering programmed cell death (26). Conversely, animal experiments have shown that selective inhibition of both nNOS (using 7-nitroindazol) and iNOS (using aminoguanidine) separately reduces cerebral infarct volume in rodents (27,28). Also nNOS and iNOS gene knock-out mice develop smaller cerebral infarcts than wild-type mice when exposed to an identical cerebral ischemic insult (29,30).

Early (2 or 4 hours) postoperative plasma concentrations of NOx may be a useful biomarker for subsequent development of new cognitive deficit. A threshold of 22 µg/L at 2 or 4 hours after surgery offers 100% specificity but less (40% and 37.5%, respectively) sensitivity. Its positive and negative predictive values are 100% and either 73% or 70.5% (for 2 and 4 hours postoperatively, respectively).

Although the origin of an increased preoperative plasma concentration of NOx in the deficit group remains unclear, baseline plasma concentrations of NOx >22 µg/L predicted early POCD with a sensitivity of 33%, a specificity of 91%, and positive and negative predictive values of 71% and 68%, respectively. Although no reliable neuroprotective intervention is available at present, a preoperative predictor could influence the decision to undergo surgery.

Similar to our results, increased serum concentrations of S-100ß protein were found after general surgical (5) and major orthopedic procedures (31). There was no correlation between serum concentrations of S-100ß and neuropsychological outcome in the latter. Although a trend toward larger S-100ß serum concentrations was noted in the deficit compared with the nondeficit group, this did not reach statistical significance in our study. A positive association between S-100ß and POCD has been described after noncardiac surgery: larger serum concentrations of S-100ß protein were present 30 minutes postoperatively in patients with POCD (n = 48, median 0.24 ng/mL, range 0.01–3.3 ng/mL) compared with those without POCD (n = 69, median 0.14 ng/mL, range 0–1.34 ng/mL, P = 0.01) (5). One explanation for this inconsistency with our results is that the mechanism underlying a deficit after less invasive surgery may differ from that following the procedures studied by Lin-stedt et al. (5).

The main concern regarding the use and application of the RC method in this clinical population is the requirement that the reference values be derived from an appropriate control group. The most appropriate control group for comparison with patients undergoing surgery has not been defined. We selected patient spouses as the control group because the effects of practice and relieved distress after an operation may be controlled for, as both patients and spouses are exposed to similar stressors associated with the operation and daily life (13).

Another limitation of this study is that the source of stable NO degradation products was not identified. Although an association between CSF and plasma concentrations of NO oxidation products has been demonstrated in patients with head injury (11), the origin of NO in this clinical setting remains somewhat speculative.

In conclusion, we have demonstrated that perioperative plasma concentrations of NO products are associated with early cognitive deficit after laparoscopic surgery. As this applies to preoperative (as well as intra- and postoperative) values, the potential exists to define a reliable biochemical predictor of POCD.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication May 5, 2004.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press