Postoperative cognitive dysfunctions (POCD) occur in 10-60% of patients undergoing surgery under general anaesthesia. The implicated causes of POCD include emotional stress, hypoxic episodes, cerebral microthrombosis, arterial hypotension, as well as kind of surgery and anaesthetics [1]. Changes in cognitive function frequently complicate the postoperative course in the elderly patients, yet are observed in all age groups. They are considered to be apoptosis-related [2, 3, 4, 5].

The aim of the study was to determine the influence of general anaesthetics on children’s memory and effectiveness of piracetam for prevention of postoperative cognitive dysfunctions.

METHODS

The study was approved by the Ethical Committee of Kharkiv National Medical University and involved children patients scheduled for maxillofacial surgery under general anaesthesia. All children were premedicated with atropine and diazepam. According to the anaesthetic used, patients were divided into the following groups: K – ketamine alone, KH – ketamine and hydroxybutyrate (HB), TH – thiopentone and HB, PH – propofol and HB.

In group K, children were not intubated and during anaesthesia were breathing spontaneously with air. In the remaining groups, following suxamethonium administration children were intubated and lungs ventilated using the air/oxygen mixture (FIO2 – 0.3). Anaesthesia was maintained using sodium hydroxybutyrate and fentanyl; pipecuronium bromide was given for muscle relaxation.
After the completion of anaesthesia the study group of patients received intravenous piracetam 30 mg kg-1 and the control group – placebo.

The cognitive functions of all children were examined preoperatively and within 10 consecutive postoperative days using the ten-words test. They were asked to recall ten short nouns either immediately after verbal presentation (short-term memory) or after 30 min (long-term memory). For short-term memory evaluation, the test was repeated three times to avoid distractions (6, 7, 8). The results were presented as percentage of preoperative values.

RESULTS

The study involved 260 children aged 7-18 years. The study group consisted of 123 patients, the control one – of 137 (Table 1).

For maintenance of anaesthesia in group K ketamine was used in the dose of  4.5±1.7 mg kg-1 (study group) and 4.6±1.7 mg kg-1 (control group) whereas in group KH, PH and TH sodium hydroxybutyrate in the dose of 75.7±15.2 mg kg-1 and 81.2±10.3 mg kg-1, respectively.

The immediate recall of ten words decreased to 70% of the preoperative value and was restored during the ten postoperative days in the control group (Fig. 1). The delayed recall of ten words decreased to: 37% of the preoperative value in group TH, 42% in group PH, 50% in group KH and 60% in group K. This cognitive function did not return to the preoperative value during ten postoperative days in the control group (Fig. 2).

The immediate recall of ten words after anaesthesia in group K was better in the study (with piracetam) than in the control group. This cognitive function restored on postoperative day 3 in the study group and on day 10 in the control group (Fig. 3). The intergroup difference in delayed recall of ten words after ketamine anaesthesia was 10-20% during the first week and reached 100% on postoperative day 9 (Fig. 4).

The immediate recall of ten words after ketamine and SH anaesthesia did not decrease below the preoperative value in the study group; however, it decreased to 70-90% of the preoperative value in the control group (Fig. 5). The delayed recall of ten words was very low during ten days in the control group. In the study group, this cognitive function was 14% below the preoperative value on day 2, and on all other days it was 10%-50% higher than the preoperative value (Fig. 6).

The moderate decline of immediate recall of ten words was observed in the control group after PH anaesthesia. Piracetam improved this memory function (Fig. 7).

The maximum reduction of delayed recall of ten words (to 40% of preoperative value) was registered on day 5 after PH anaesthesia in the control group. In the study group, it decreased to 75% of the preoperative value on day 2. This memory function restored to the preoperative value on day 7 in the study group and remained at 82% of the preoperative value on day 10 in the control group (Fig. 8).

After TH anaesthesia, the immediate recall of ten words was higher in the study group than in the control group during ten days (Fig. 9). In the control group, the delayed recall of ten words was most severely impaired on day 1 and 2 and remained below the preoperative level for ten postoperative days. Piracetam improved this cognitive function after TH anaesthesia (Fig. 10).

DISCUSSION

In clinical practice, it is difficult to determine the exact cause of POCD. Assuming that stress, pain and brain damage factors are not involved, psycho-injuring effects of general anaesthesia ought to be considered.

Russian investigators found that memory indexes in children with upper lip and palate cleft were not fully restored within two months after ketamine anaesthesia and two weeks after halothane anaesthesia [9]. Ketamine was found to be dangerous for memory and intellectual indexes of patients and some authors recommended excluding ketamine from anaesthesia practice [10]. Others reported a moderate decline of cognitive functions after ataractanalgesia with thiopentone, fentanyl and diazepam and effectiveness of thiocetam for prevention of POCD [11].

In our earlier study, ketamine was demonstrated to be more dangerous for cognitive functions of children than propofol [12]. On the other hand, we did not find literature data concerning the influence of sodium hydroxybutyrate on such functions. This agent is widely used in post-Soviet countries for maintenance of anaesthesia. Due to delayed maximal hypnotic effect, sodium hydroxybutyrate is not used for induction. However, as an agonist of GABAergic receptors it has some side effects, e.g. epileptogenic and intracranial pressure-increasing ones.

In the present study, declines in memory indexes of children aged 7-18 years were observed after administration of ketamine alone and co-administration of sodium hydroxybutyrate with ketamine, propofol and thiopentone. The most injured memory function was the delayed recall of ten words, which indicates the fixation of information in memory. This memory function was most affected on day 5-6 after anaesthesia. The intravenous administration of piracetam after general anaesthesia improved memory indexes.

Piracetam affects neuronal metabolism, improves utilization of glucose in neurons. It also improves the synthesis of neuromediators and nucleic acids in the brain. These mechanisms may be important for prevention of postoperative cognitive dysfunctions after general anaesthesia in children.

The mechanism by which anaesthetic agents induce general anaesthesia has not been fully understood. Some authors hypothesized that propofol decreased neuronal activity by retracting neuronal neurites. An experimental study demonstrated that cultured cortical rat neurones retract their neurites after exposure to propofol in a concentration- and time-dependent manner [13].

Moreover, the early exposure to common anaesthetic agents (midazolam, nitrous oxide and isoflurane) causes widespread neurodegeneration in the developing rat brain and persistent learning deficits [14].

Inhalation anaesthetics may induce cell damage by causing abnormal calcium release from the endoplasmic reticulum via excessive activation of inositol 1,4,5-tris-phosphate receptors. Isoflurane has greater potency than sevoflurane or desflurane to induce such injuries [15].

Co-administration of ketamine plus propofol or ketamine plus thiopentone or a high dose of propofol alone significantly triggered apoptosis. Neonate mice exposed to a combination of anaesthetic agents or ketamine alone displayed disrupted spontaneous activity and learning. The anxiolytic action of diazepam was less effective when given to adult mice neonatally exposed to propofol. The study showed that both a gamma-aminobutyric acid type A agonist (thiopentone or propofol) and an N-methyl-d-aspartate antagonist (ketamine) during a critical stage of brain development potentiated neonatal brain cell death and resulted in functional deficits in adulthood. The use of thiopentone, propofol and ketamine individually elicited no or only minor changes [16].

Classes of general anaesthetics with distinct clinical profiles appear to induce amnesia, hypnosis, and immobility via different molecular targets. Solt and Forman suggest that the understanding the mechanisms underlying the therapeutic and toxic actions of anaesthetics helps us reframe the ‘art’ of anaesthesia into more of a ‘science’ [17].

CONCLUSIONS

1. General anaesthesia using ketamine, ketamine and sodium hydroxybutyrate, thiopentone and sodium hydroxybutyrate or propofol and sodium hydroxybutyrate affects memory functions in children.

2. Fixation of information in memory is the most affected cognitive function after general anaesthesia.

3. Piracetam is effective for prevention of postoperative cognitive dysfunctions after general anaesthesia in children.

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REFERENCES

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12.Khizhniak ??, Fesenko U?: The influence of ketamine and propofol-based anesthesia on cognitive functions of children after maxillofacial surgery.Ukrainian Herald of Psychoneurology 2001; 9: 106-108.

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14.Jevtovic-Todorovic V, Hartman RE, Izumi Y: Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neuroscience 2003; 23: 876-882.

15.Yang H, Liang G, Hawkins BJ, Madesh M, Pierwola A, Wei H: Inhalational anesthetics induce cell damage by disruption of intracellular calcium homeostasis with different potencies. Anesthesiology 2008; 109: 243-250.

16.Fredriksson A, Pontén E, Gordh T, Eriksson P: Neonatal exposure to a combination of N-methyl-d-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 2007; 107: 427-436.

17.Solt K, Forman SA: Correlating the clinical actions and molecular mechanisms of general anesthetics. Curr Opin Anaesthesiol 2007; 20: 300-306.

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Address:

*Ulbolgan A. Fesenko
Kharkiv National Medical University
4 Lenin Avenue Kharkov, 310022 Ukraine
e-mail: vfesenko@yahoo.com

Received: 14.10.2008.
Accepted: 26.02.2009.