Absence of memory for intra-operative information during surgery with total intravenous anaesthesia{dagger}

I. F. Russell1 and M. Wang2

1Department of Anaesthesia, Hull Royal Infirmary, Anlaby Road, Kingston upon Hull HU3 2JZ, UK. 2Department of Clinical Psychology, University of Hull, Cottingham Road, Kingston upon Hull HU6 7RX, UK*Corresponding author

{dagger}This study was initially presented at the Fourth International Symposium on Memory and Awareness in Anaesthesia, held at Northwick Park on July 10–12, 1998; an abbreviated form of the results was published in the book of abstracts from that meeting.

Accepted for publication: October 5, 2000


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
While using the isolated forearm technique, we wished to determine whether patients who did not respond to commands during general anaesthesia with a total intravenous technique (propofol and alfentanil with atracurium) had any evidence of post-operative explicit or implicit memory. Forty women undergoing major gynaecological surgery were randomized, in a double-blind design, to hear two different tapes during surgery. Psychological tests of explicit and implicit memory were conducted within 2 h of surgery. There was no evidence of implicit or explicit memory, nor any recall, in the seven women who responded to commands during surgery. We conclude that during total intravenous anaesthesia with propofol and alfentanil, there is no evidence that learning takes place when anaesthesia is adequate. Furthermore, with this anaesthetic technique, it would seem that—provided any period of patient responsiveness is short and that unconsciousness is induced rapidly again—there is no evidence of implicit or explicit memory.

Br J Anaesth 2001; 86: 196–202

Keywords: anaesthesia, depth; anaesthesia, general; memory; measurement techniques, isolated arm; anaesthetics i.v., propofol


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Many publications suggest that patients can recall information presented to them during surgery; these studies are discussed in detail in several reviews.14 However, while there is agreement that memory for new information exists after surgery, there is debate as to the level of consciousness of the patients when the intra-operative information was presented to them (i.e. were the patients adequately anaesthetized?). Merikle and Daneman3 performed a meta-analysis of the literature and stated that there is ‘considerable evidence that specific information is both perceived during anaesthesia and remembered following surgery’. However, the authors assume that ‘patients who are undergoing general anaesthesia are ... unconscious of all external events for the entire duration of surgery’. The studies included in the meta-analysis provide no evidence that patients were in fact anaesthetized (i.e. unconscious and unresponsive) when information was presented. This is a problem with much research in this area. Andrade2 states that during ‘clinically adequate anaesthesia it is not yet clear that patients were actually unconscious when stimuli were presented’. At present the only direct method of detecting a responsive state during surgery is the isolated forearm technique (IFT). By using a tourniquet on one arm to prevent muscle relaxants paralysing the hand muscles, the IFT allows a patient to respond, should they become conscious during surgery, to verbal commands such as ‘Open and close the fingers of your right hand.’59 All electronic brain monitors assess consciousness indirectly and the IFT is the ‘gold standard’ against which all such monitors must be tested.10 11 Use of the IFT has shown that some patients can respond to commands during surgery without any other outward sign of responsiveness.59 If patients are given information during such an awake responsive state, it would not be surprising that sophisticated psychological tests detected evidence of memory for this information after surgery.

A previous study using the IFT with inhalational anaesthesia (nitrous oxide and halothane) found no evidence of post-operative recall for information presented to patients at a time when they were unresponsive to commands.9 Investigations of total intravenous anaesthesia (TIVA) with etomidate7 and midazolam8 found 7% and 72% incidence of responsiveness, respectively, during surgery compared with zero incidence during inhalational anaesthesia.9 It has been argued that awareness is a greater risk with TIVA than with inhalational anaesthesia.12 13 With the growing popularity of propofol-based TIVA, we wished to study the incidence of intra-operative responsiveness of patients anaesthetized with this technique and also if patients could recall information presented during surgery at a time when the patient was known to be unresponsive to commands. Nordstrom and colleagues14 described a simple TIVA regimen using only one infusion pump and, equally importantly, they also provided data on the incidence of post-operative recall (5/2500). With such a well documented incidence of recall, we decided to base our study on this regimen.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Approval for the study was obtained from the Hull and East Yorkshire ethics and clinical trials committee. The purpose of the trial was explained to women with no hearing difficulty presenting for major gynaecological surgery; their informed consent was obtained. After premedication with oral temazepam 20 mg, 1–2 h before surgery, the women were brought to the anaesthetic room. Intravenous access was obtained in the non-dominant arm with a 17 gauge cannula. An epidural catheter was then placed at L2/3 through an 18 gauge needle (lateral oblique approach, loss of resistance to 1 ml of 0.5% bupivacaine) and, after a negative aspiration test, a further 14–19 ml of 0.5% bupivacaine was injected incrementally over 5 min. The patient was then taken into the operating theatre, the various monitors were attached and, after a short period of baseline monitoring, general anaesthesia was induced.

The general anaesthetic was based on the propofol/alfentanil infusion regimen described by Nordstrom and colleagues.14 Propofol and alfentanil were mixed in the same syringe as follows: propofol 500 mg plus alfentanil 2500 µg to a total volume of 55 ml, giving final propofol and alfentanil concentrations of 9.1 mg ml–1 and 45.5 µg ml–1, respectively. Induction and anaesthesia were based on the propofol delivery from this mixture, with alfentanil in proportion. Induction was with propofol 2–2.5 mg kg–1, infused at a rate of 600 ml h–1 and maintenance was a 10, 8, 6, 4 mg kg–1 h–1 stepdown (at 10 min intervals) infusion regimen. The propofol/alfentanil infusion was controlled by a Graseby 3400 infusion pump (Graseby Medical Ltd, Watford, UK) and a multilumen extension tube with non-reflux valves (Vygon Octopus; Vygon, Ecouen, France) was included between the infusion lines and the intravenous cannula to prevent backflow. Suxamethonium 1–1.5 mg kg–1 was administered and endotracheal intubation was performed. When the action of suxamethonium began to wear off, atracurium 0.2–0.4 mg kg–1 was used for more prolonged neuromuscular block. The lungs were ventilated with an air–oxygen mixture containing 35–40% oxygen through an Oxford Penlon mark II ventilator in its non-rebreathing configuration and end-tidal carbon dioxide was maintained between 4 and 5%.

For each patient, two identical looking 1 min continuous-loop cassette tapes (coded ‘FG’ for fruit group or ‘VG’ for vegetable group on the underside) were prepared by I.R. One to two minutes after skin incision, one of these tapes was played to the patients in a randomized double-blind manner. Randomization was achieved by means of codes contained in consecutively numbered brown envelopes. A colleague who was not involved in the trial had previously written the codes on to cards (20 cards for each code) and placed the cards individually into the envelopes. The envelopes were then mixed and numbered consecutively 1–40. During the trial the anaesthetic assistant opened the envelopes, wrote the envelope number and the name of the patient on each card and kept the cards in a large brown envelope until the trial was completed. The appropriate tape was chosen by the assistant, according to the code on the card, and placed in a tape recorder (Sony Professional Walkman). The remaining tape was kept hidden until the end of surgery when both tapes were then placed back in their identical plastic cases by the assistant. The tapes were personalized for each patient by inclusion of her preferred name before the command and the information. Each tape contained the same initial message which included the patient’s preferred name: [Name], [Name], this is Dr Russell speaking. If you can hear me, open and close the fingers of your right hand, open and close the fingers of your right hand.’ The second message differed between the tapes. One tape contained the information ‘[Name], [Name], this is Dr Russell speaking. Here are some special words I’d like you to remember: green pear, sharp lemon, sour gooseberry.’ The second message on the other tape was ‘[Name], [Name], this is Dr Russell speaking. Here are some special words I’d like you to remember: frozen peas, butter beans, Chinese leaves.’ To ensure that the patients heard no other extraneous information through the open dynamic headphones (Beyerdynamic DT 411), the 15 s intervals between the voice messages consisted of loud radio static.

If hand movements were observed during surgery, the tape was immediately switched off and the patient spoken to directly. The patients were reassured and then the hand responses to direct commands (e.g. ‘Squeeze my fingers’) and to conditional commands (e.g. ‘If you are in pain, squeeze my fingers twice’ followed by ‘If you are comfortable, squeeze my fingers once’) were assessed. Anaesthesia was then deepened with a bolus of the propofol/alfentanil mixture (equivalent to propofol 0.5 mg kg–1) and the infusion rate was increased by the equivalent of propofol 1 mg kg–1 h–1 before the tape was switched on again. The infusion rate was then stepped down by 1 mg kg–1 h–1 at 10 min intervals.

At the end of surgery, the tape was switched off of at the same time as the propofol/alfentanil mixture, muscle relaxant was reversed as required with atropine/neostigmine (0.6 mg/1.2 mg) and the epidural was topped up with 10 ml of 0.125% bupivacaine containing diamorphine 3 mg.

Within 2 h of the end of surgery, the patients were questioned by I.R. for evidence of explicit or implicit memory. All patients were asked the same questions, without prompting, in the following order: (i) Do you remember coming into the anaesthetic room? (ii) Do you remember the epidural being inserted? (iii) Do you remember the sticky electrodes being placed? (iv) Do you remember going into the operating theatre? (v) What was the last thing you remember before going to sleep? (vi) What was the first thing you remember on waking up? (vii) Can you remember anything in between these two? (viii) Did you have any dreams? (ix) Tell me the first five fruits you can think of. (x) Tell me the first five vegetables you can think of. (xi) Now I want you to tell me the first word that comes into your head when I say a word to you: father, green, sharp, sour, frozen, butter, Chinese.

Isolated forearm technique
Padding was placed around the dominant forearm (usually right) and an isolating tourniquet cuff wrapped around this. The standard arterial pressure cuff for routine monitoring of arterial pressure was placed on the dominant upper arm and the arm was placed on an arm board where it could be clearly observed. To restrain the hand from sudden unexpected movements, a tie was placed lightly around the fingers and the arm board. A Datex Relaxograph was used to check neuromuscular transmission under and distal to the cuff. Stimulating electrodes were placed over the ulnar and median nerves at the elbow while the sensing electrodes were placed at the wrist and over the hypothenar eminence. As soon as consciousness was lost (as judged by absence of response to command), neuromuscular transmission was checked by observing the hand contractions as the Relaxograph went through its initial set-up procedure. When the paralysis after the intubating dose of succinylcholine began to wear off, the isolating cuff was inflated just before giving atracurium. The cuff remained inflated for 20 min before deflation. Whenever further atracurium was required, this same inflation/deflation process was followed. Neuromuscular transmission under and distal to the tourniquet was confirmed by observation of the hand and finger responses to the ‘train of four’ stimuli delivered every 20 s from the Relaxograph. Although the Relaxograph assesses the electrical activity of muscle groups, it was the observed hand responses that were of importance in ensuring that neuromuscular transmission was sufficient for the patient to respond.

Chi-squared tests and signal detection analysis15 were used as appropriate.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Forty women were recruited into the study. Their ages, weights and duration of tape exposure, together with an indication of the surgical procedures, are shown in Table 1. The difference in the mean duration of tape exposure in the two groups just failed to reach statistical significance (P=0.06). This difference was almost entirely due to one patient in the ‘fruit’ group undergoing very long surgery (lasting 280 min, 2.8 SDs above the mean).


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Table 1 Age, weight and tape duration for the two groups together with the type of surgery. {dagger}Mean (range). *Mean (SD)
 
No patient had explicit memory for any aspect of surgery or of the taped commands. Tables 2–6 indicate the results of tests of implicit memory from all 40 patients. These tables provide the ‘hits’ data and serial position scores for lists of both three and five exemplars. In the word association test (Table 6), there was only one ‘hit’, the word pair ‘frozen peas’.


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Table 2 Number of vegetable and fruit exemplar ‘hits’ when a list of five exemplars was requested; the total number of possible ‘hits’ is 60
 

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Table 6 Word association ‘hits’. Total possible hits per group was 60. *All seven of the word association ‘hits’ were ‘frozen peas’
 
Seven women, two in the ‘fruit’ group and five in the ‘vegetable’ group, responded to commands at some stage during surgery. Among them, these women responded a total of 12 times at propofol infusion rates ranging from 4 to 7 mg kg–1 h–1 and at times ranging from 34 to 125 min into surgery (Table 7). On only one occasion did one of these women express her discomfort (Table 7). There was no evidence that these seven patients had a greater rate of recall than non-responding patients (Table 8).


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Table 7 Group allocation and weight of patients who responded to commands, the times of the responses and the infusion rates at the time of the responses from seven patients with verified responses to commands. *At this time the patient indicated she was uncomfortable; the surgeon had just inserted a self-retaining retractor and was performing a thorough exploration of the upper abdominal cavity
 

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Table 8 Number (proportion of total possible) of hits in those patients awake and responding during surgery compared with patients who did not respond during surgery. *This difference is not significant (P=0.48)
 
None of the women had any side effects from the use of the isolating tourniquet.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
There is debate about whether familiar or unfamiliar words are more likely to be returned in memory tests,2 so to cover both possibilities the exemplars presented to our patients spanned a wide range: from third through seventh to below fifteenth in their respective lists (the position of the exemplars in their respective lists had previously been established in our population of women presenting for major gynaecological surgery16). We asked each patient for five exemplars and analysed both three-exemplar and five-exemplar lists. This allowed a wider range of familiarity/unfamiliarity to be assessed, increasing the chances of a positive effect. Despite this, we found no evidence of explicit or implicit memory for information presented during surgery under general anaesthesia. This result confirms previous published8 9 and as yet unpublished studies11 from this department but is contrary to many other results discussed in reviews.14

One possible reason for our negative findings could be that the memory tests we used were unsuitable. We do not believe this is a valid reason. In a literature review carried out in 1990,16 seven studies were found which investigated word priming during general anaesthesia. Three of these studies obtained statistically significant evidence of word priming; in contrast to the four negative studies, these three positive studies used category association to cue recall of implicit memory. Hence this method (category association) was chosen for the current study. In addition, our experimental design uses two different probes (category association and word pair association) to cue the same primed words to increase the chances of obtaining an effect. No statistical adjustment was employed for these multiple tests, thus increasing the probability of a type I error but, despite this, we did not obtain significant results.

Other possible factors to consider which could contribute to the lack of recall are the early post-operative testing and the use of temazepam premedication. The effects of temazepam on memory in this situation have not been studied but all patients remembered being in the anaesthetic room and having the epidural catheter inserted, they all remembered the attachment of electronic monitoring electrodes and being taken into the operating theatre and placed on the operating table. In previous studies, temazepam was used as premedication when patients had recall.7 9 One could argue that the presence of residual temazepam in the immediate post-operative period should increase the probability of recall because of state-dependent memory effects. Our patients were fully responsive to verbal command and conversation at the time of testing and other researchers, using similar testing, found implicit memory when patients were tested 30–179 min after operation.17 In their meta-analysis, Merikle and Daneman3 found that early testing was strongly associated with significant implicit memory effects. We believe we tried to favour conditions that would increase the probability of finding evidence for a priming effect.

The most likely reason why we did not find priming is that anaesthesia was adequate. With the IFT we knew whether patients were responsive or not when the information was being played to them. In the majority of memory studies unconsciousness has either been assumed or been determined based on ‘normal’ clinical signs. In the presence of muscle relaxants, it is difficult to assess the depth of anaesthesia. The usual clinical signs of anaesthesia (heart rate, arterial pressure, sweating, tear production) are unreliable indicators of consciousness during surgery.1820 Virtually all the original clinical signs described by Snow21 and developed by Geudel22 rely on muscle activity: cardiovascular signs are not mentioned. When muscle relaxants are used, these original clinical signs are of limited, if any, value. The origins of using cardiovascular indices to gauge depth of anaesthesia are unclear and we are not aware of any study which has shown them to be of value in detecting consciousness. On the other hand, several studies using different anaesthetic techniques in conjunction with the IFT have shown clearly that clinical signs cannot be used to predict whether or not patients are awake and responsive during surgery.79 23 In addition, experienced anaesthetists could not distinguish the anaesthetic records of patients known to have suffered awareness with recall from the records of patients with no evidence of awareness and recall.19

One previously very widely used anaesthetic technique (nitrous oxide, narcotic, muscle relaxant) may be associated with >50% of patients being awake during surgery but with no conscious recall for this fact after surgery7 and this anaesthetic technique has been used for all or a large proportion of the patients in some studies of memory and recall which indicate post-operative implicit memory for intra-operative information.17 2426 In the meta-analysis by Merikle and Daneman,3 eight of the nine studies that found evidence for post-operative recall of intra-operative information used an anaesthetic technique based around muscle relaxants (the ninth study did not provide anaesthetic details) and depth of anaesthesia was gauged by clinical monitoring. In the 16 investigations that found no evidence for recall, nine used a relaxant anaesthetic technique, in four the patients breathed spontaneously and in five the anaesthetic technique could not be defined. It is notable that all the spontaneous respiration studies were in the negative outcome group.

In their meta-analysis, Merikle and Daneman3 concluded that unconscious patients perceive information and remember it after surgery. However, in reaching this conclusion they stated that, ‘Despite the remote possibility that some patients may experience moments of awareness during anaesthesia, we believe it is reasonable to assume that patients who are undergoing general anaesthesia are in fact unconscious of all external events for the entire duration of surgery.’ The results of IFT studies79 23 indicate that ‘the possibility that some patients may experience moments of awareness during anaesthesia’ is far from remote and the assumption ‘that patients are unconscious of all external events for the entire duration of surgery’ cannot be made: with some ‘anaesthetic’ techniques a significant proportion of patients are awake. This is acknowledged by Andrade,2 where she points out in the conclusion of her very extensive and exhaustive review of the subject that ‘although the studies discussed in this article deal with learning during "clinically adequate" anaesthesia, it is not clear that patients were actually unconscious when stimuli were presented’. Thus while studies in which the IFT has not been used indicate that patients can remember information presented during surgery, without direct evidence that patients were adequately anaesthetized, these results cannot be used to indicate recall for information presented during anaesthesia.

It is widely accepted that evidence of memory after surgery may reflect moments of intra-operative arousal, but it is still felt that such arousal ‘is difficult to prove because there is no practical tool—to predict or identify awareness during anaesthesia’.27 Lack of knowledge of the conscious state of patients is a fundamental problem when investigating memory and anaesthesia. Why is the IFT (which has been known about for >20 yr) not used to detect awareness during surgery? We believe it may be thought that the technique is unreliable or that studies using the IFT are difficult to interpret because of practical and technical problems.28 Criticisms of the IFT include the following: (i) response to command using the IFT correlates poorly with clinical signs of light anesthesia;29 (ii) the IFT can only be used for 20 min as the arm will become paralysed;12 30 (iii) it is difficult to distinguish purposeful arm movements from reflex movements;25 28 3032 (iv) the response to command does not indicate that the patient is conscious;10 28 30 32 33 and (v) the IFT response does not correlate with recall.10

These criticisms represent a fundamental misunderstanding of the IFT which has been discussed in detail.11 23 If a patient responds to commands during surgery, then this is a clear indication that the patient is not unconscious—irrespective of the clinical signs. In these circumstances it is the clinical signs which are unreliable, not the IFT. It is precisely for this reason that the IFT has been described as the gold standard for assessing consciousness during general anaesthesia in the presence of muscle relaxants.10

The 20 min limit on the use of the IFT is a widespread misconception and arises from a belief that the 20 min limit for inflation of the tourniquet is the end of the IFT. If doses of muscle relaxant are selected carefully, there is no time limit to the duration of the IFT.11 23 Table 7 shows that there is no 20 min limit on the use of the IFT.

The criticism that it is difficult to distinguish between reflex and purposeful movements of the arm is based entirely on two studies where no attempts were made to distinguish between these two types of movement: movements of the hand were merely observed.25 31 The two types of hand movement can be readily distinguished by directly asking the patient to respond in a particular manner.11 23 34

The definition of consciousness has been much debated but, in simple terms, we do not believe that a patient responding to conditional commands during surgery can be described as unconscious.

It is true that IFT responses do not correlate well with recall, but this is to be expected. It is well recognized in volunteer studies using nitrous oxide,35 isoflurane36 or propofol37 that subjects under the influence of low doses of these drugs may be conscious and responsive to commands yet, later, have no explicit or implicit memory for these commands. When using the IFT during surgery, most patients begin to respond to commands at a level of consciousness where the information is either not stored in memory or is stored in such a manner that it cannot be recalled after surgery. The exact conditions required for memory to be stored in a retrievable manner are not known, but it is possible that memory will start to be ‘laid down’ if anaesthesia continues to lighten or if there is a period of more intense surgical stimulation while the patient is responding.

The studies of Jelicic and colleagues24 38 show the difference between an inadequate and an adequate anaesthetic technique on the results of identical memory studies. With a relaxant–nitrous oxide–narcotic technique, where there is a high probability of patients being awake and responsive during surgery,7 these authors found good evidence of post-operative recall for information presented during surgery.24. However, when the same testing methodology was used with a volatile anaesthetic technique and spontaneous respiration, where the likelihood of patients being awake during surgery is very low, they found no evidence of recall.38

None of the seven women in the current study who responded to commands during surgery showed evidence of explicit or implicit memory. Since propofol abolishes recall in conscious volunteers, 39 40 this finding is not surprising. These seven women had effective epidural anaesthesia and surgical stimuli would not heighten their arousal. The effect of the epidural analgesia on the incidence of responsiveness can be compared with the results of 12 women for whom data have not been presented above. These 12 women consented to the memory investigation aspects of this study but then refused epidural analgesia. Five of these 12 women (42%) awoke at propofol infusion rates between 8 and 4 mg kg–1 h–1 (the propofol/alfentanil solution in these 12 patients consisted of propofol 500 mg mixed with alfentanil 5000 µg to a total volume of 60 ml14). Thus the overall incidence of intra-operative wakefulness in all 52 patients was 21%, with none having post-operative recall. This compares with the rate of 0.2% for post-operative recall of intra-operative events found by Nordstrom and colleagues,14 after post-operative interviews with 1000 patients anaesthetized with an almost identical technique. These authors14 concluded that ‘if the true incidence of conscious awareness is to be determined, interviews must be extended beyond the first post-operative day’. However, these authors were detecting recall, not conscious awareness. Comparison of the present study with that of Nordstrom and colleagues14 shows that there may be a wide difference in the incidence of intra-operative wakefulness and post-operative recall for that wakefulness. To date, wakefulness during surgery can only be reliably detected with the IFT.11

In conclusion, we found explicit or implicit memory of information presented during surgery under total intravenous anaesthesia with propofol and alfentanil, either when anaesthesia is sufficient to maintain patients in an unresponsive state or for short periods of responsiveness. Even when using an anaesthetic technique with a reliably estimated incidence of post-operative recall of 0.2%,14 the importance of using the IFT to detect intra-operative wakefulness is clearly shown. These results support the argument that when investigating post-operative memory for information presented while patients are anaesthetized, evidence must be provided that anaesthesia was adequate.


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Table 3 Number of vegetable and fruit exemplar ‘hits’ when a list of three exemplars was requested; the total number of possible hits is 60
 

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Table 4 Serial position score based on list of five exemplars (score=5 for first position down to 1 for fifth position). Maximum score per patient= 12 (5+4+3). Maximum score per group=240
 

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Table 5 Serial position score based on a list of three exemplars. Score=3 for first position down to 1 for third position. Maximum score per patient= 6 (3+2+1). Maximum score per group=120
 

    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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