Anesth Analg 2003;96:1692-1697
© 2003 International Anesthesia Research Society
TECHNOLOGY, COMPUTING, AND SIMULATION
The Effect of Hypothermia on Myogenic Motor-Evoked Potentials to Electrical Stimulation with a Single Pulse and a Train of Pulses Under Propofol/Ketamine/Fentanyl Anesthesia in Rabbits
Takanori Sakamoto, MD,
Masahiko Kawaguchi, MD,
Meiko Kakimoto, MD,
Satoki Inoue, MD,
Masahiro Takahashi, MD, and
Hitoshi Furuya, MD
Department of Anesthesiology, Nara Medical University, Japan
Address corresponding and reprint requests to Takanori Sakamoto, MD, Department of Anesthesiology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634–8522, Japan. Address e-mail to tsakamot{at}naramed-u.ac.jp
 |
Abstract
|
|---|
In the present study, we investigated the effect of hypothermia on myogenic motor-evoked potentials (MEPs) in rabbits. The influence of stimulation paradigms to induce MEPs was evaluated. Twelve rabbits anesthetized with ketamine, fentanyl, and propofol were used for the study. Myogenic MEPs in response to electrical stimulation of the motor cortex with a single pulse and a train of three and five pulses were recorded from the soleus muscle. After the control recording of MEPs at 38°C of esophageal temperature, the rabbits were cooled by surface cooling. Esophageal temperature was maintained at 35°C, 32°C, 30°C, and 28°C, and MEPs were recorded at each point. MEP amplitude to single- pulse stimulation was significantly reduced with a re-duction of core temperature to 28°C compared with the control value at 38°C (0.8 ± 0.4 mV versus 2.3 ± 0.3 mV; P < 0.05), whereas MEP amplitude to train-pulse stimulation did not change significantly during the cooling. MEP latency was increased linearly with a reduction of core temperature regardless of stimulation paradigms. In conclusion, these results indicate that a reduction of core temperature to 28°C did not influence MEP amplitudes as long as a train of pulses, but not a single pulse, was used for stimulation in rabbits under propofol/ketamine/fentanyl anesthesia.
IMPLICATIONS: Intraoperative monitoring of myogenic motor-evoked potentials (MEPs) may be required under hypothermic conditions because of its neuroprotective efficacy. However, data on the influence of hypothermia on myogenic MEPs are limited. The results indicate that multipulse stimulation may be better than single-pulse stimulation when monitoring MEPs during hypothermia.
|
Introduction
|
|---|
Paraplegia remains a devastating complication of thoracic and thoracoabdominal aortic surgery with reported incidence ranging from 5% to 40% (1). Although the underlying mechanisms of paraplegia are multifactorial, intraoperative spinal cord ischemia plays a fundamental role. Therefore, an early and precise detection of spinal cord ischemia should be the essential key to prevent paraplegia. Myogenic motor-evoked potential (MEP) is a strong candidate for such intraoperative monitoring because it provides a method for monitoring the functional integrity of descending motor pathways (2). However, myogenic MEPs elicited by single-pulse stimulation are very sensitive to suppression by most anesthetics (3–8). Recently, to overcome anesthetic-induced depression of myogenic MEPs, multiple-stimulus setups with paired or a train of pulses for stimulation of the motor cortex have been proposed (9–15). Several investigators have demonstrated that intraoperative MEP monitoring with multipulse stimulation is a useful adjunct to prevent paraplegia after thoracoabdominal aortic surgery (16–18).
Investigations in animals have shown that mild to moderate hypothermia is associated with a substantial decrease in histological damage in models of spinal cord ischemia and injury (19–21). Hypothermic therapy has been indicated during procedures such as thoracoabdominal aortic replacement in which the spinal cord is susceptible to ischemia and injury (1). MEP monitoring may therefore be required under hypothermic conditions during such operations. Although electrophysiological monitoring is highly sensitive to changes in body temperature, data on the influence of hypothermia on myogenic MEPs are limited (22–24). This study was therefore conducted to investigate the effect of hypothermia on myogenic MEPs in rabbits. To induce MEPs, a single pulse or a train of three or five pulses were used for stimulation of motor cortex.
|
Materials and Methods
|
|---|
Twelve male New Zealand white rabbits weighing 2.0–2.5 kg (mean, 2.3 kg) were used in this study. They were housed and maintained on a 12-h light-dark cycle with free access to food and water. The study was approved by the Animal Experiment Committee of Nara Medical University.
The rabbits were given 50 mg/kg of ketamine IM, and a 24-gauge catheter was placed in the right marginal ear vein. Thereafter, a continuous infusion of 25 mg · kg-1 · h-1 of ketamine and 30 µg · kg-1 · h-1 of fentanyl in lactated Ringer’s solution was initiated at a rate of 4 mL · kg-1 · h-1. Another 24-gauge catheter was inserted in the left ear vein for the administration of propofol. The trachea was intubated via a tracheostomy, and the lungs were ventilated mechanically to maintain end-tidal carbon dioxide at 30–35 mm Hg. End-tidal concentrations of carbon dioxide were continuously monitored by a gas analyzer (Hewlett Packard, Andover, MA). The left femoral artery was exposed and cannulated for arterial blood pressure monitoring and blood gas analysis. Blood gases, pH, and hematocrit were measured with a blood gas analyzer (GEM premier, Mallinckrodt, Ann Arbor, MI). The values for pH, PaO2, and PaCO2 were not corrected for temperature (
-stat management).
The rabbits were turned prone, and the head was fixed in a stereotactic frame. The scalp was infiltrated with 1% lidocaine and reflected laterally to expose the calvarium. Two small craniotomies were performed with an air drill. A point 0.5 mm lateral to the sagittal suture and 14.5 mm rostral from the lamboid suture on the left hemisphere was chosen as an anodal stimulating site. A point 0.5 mm to the right of the sagittal suture at the level of the lamboid suture was used for the cathode. Silver ball electrodes (1 mm in diameter) were placed epidurally via the holes, into which mineral oil was applied. Two standard recording needle electrodes were inserted in the left soleus muscle. A ground electrode was set at the tail. Constant voltage anodal stimulation was delivered through an electrical stimulator (SEN-3301, Nihon Kohden, Tokyo, Japan). The strength of the electrical stimulus was gradually increased until the MEP amplitude no longer increased. The recording device (Neuropack sigma; Nihon Kohden, Tokyo, Japan) was triggered by the stimulating device. Low-cutoff and high-cutoff filters were set at 30 Hz and 3 kHz, respectively. Amplitude was defined as the voltage from the most negative component to the most positive component of the evoked electromyographic activity. Values were averaged from three to five individual responses. MEPs in response to single-pulse, three-pulse, and five-pulse stimulations were recorded. The duration of each pulse was 200 µs. The interpulse interval during multiple-pulse stimulations was set at 2 ms. The interval between successive measurements was 60 s.
After the setting of MEP measurements was completed, a bolus of 10 mg/kg of propofol was administered followed by a continuous infusion of propofol at a rate of 0.8 mg · kg-1 · min-1. Esophageal temperature was continuously monitored with a thermometer (Mon-a-Therm, Mallinckrodt, St Louis, MO) and adjusted to 38°C. Thirty minutes after the bolus infusion of propofol, control MEPs were recorded at 38°C. Then, surface cooling was initiated by irrigating the water mattress with cold water (4°C). The mattress was set around the body trunk but was not attached to the limbs directly. Target esophageal temperatures were then set at 35°C, 32°C, 30°C, and 28°C. After target temperature was maintained for 10 min, MEPs were recorded in the same fashion as described above at each point. MEP amplitudes were converted to percentages of the control MEP amplitude (%MEP amplitude).
To measure the blood concentration of propofol, blood was collected via an arterial line at each target temperature in four rabbits. Each blood sample was immediately centrifuged for 5 min at 3000 rpm. Serum was stored at 30°C until analysis. On the analysis day, the samples were defrosted, and then 0.2 mL of each sample was mixed with 1 mL of ethyl acetate and 0.1 mL of NaOH (50 mM), vortexed vigorously for 5 min, and centrifuged for 5 min at 15,000 rpm. Nine hundred-microliter aliquots of the supernatants were freeze-dried. The freeze-dried pellet was resolved with 0.05 mL of mobile phase and injected unto phenyl reverse-phase column (Micro Bondasphere 5-micro phenyl 100A; Waters Associates, Milford, MA). The mobile phase (100 mM of phosphate buffer [pH value of 2.8]; methanol, 6:4) was maintained at a flow rate of 0.8 mL/min by the high-performance liquid chromatography pump (655A-11; Hitachi, Japan). Propofol was detected by a UV-absorbance detector (set at 270 nm; Waters 486; Waters Associates). After all the recordings, the rabbits were killed by an injection of potassium chloride, which caused cardiac arrest.
All values are expressed as mean ± SEM. For a statistical analysis, parametrical methods were applied for all variables because a normal distribution was confirmed by the Kolmogorov-Smirnov test. Physiological variables and propofol concentration were assessed using analysis of variance with repeated measurements followed by Student-Newman-Keuls test for multiple comparisons. %MEP amplitudes and latencies were assessed using two-way analysis of variance with repeated measurements followed by Student-Newman-Keuls test for multiple comparisons. P value <0.05 was considered to be significant.
|
Results
|
|---|
Physiologic variables are shown in Table 1. Mean arterial pressure, pH, PaCO2, and PaO2 did not change significantly during the cooling. Heart rate was significantly slower at 28°C compared with that at 38°C (P < 0.05).
Control MEP amplitudes after a single pulse and a train of three and five pulses, which were measured at 38°C, are shown in Table 2. There were no significant differences among control MEP amplitudes after a single pulse and a train of three and five pulses. After single-pulse stimulation, MEP amplitude was significantly reduced at 28°C compared with the control value at 38°C (0.8 ± 0.4 mV versus 2.3 ± 0.3 mV; P < 0.05), whereas MEP amplitudes after a train of pulses stimulation remained unchanged during the cooling. Figure 1 shows the changes in %MEP amplitude after a single pulse and a train of three and five pulses during the cooling to 28°C. %MEP amplitudes after single-pulse stimulation were significantly smaller than those after a train of pulses at 28°C and 30°C (P < 0.05).
View larger version (14K):
[in this window]
[in a new window]
|
Figure 1. Changes in percentage amplitude of motor-evoked potential (MEP) after electrical stimulation of the motor cortex with a single pulse and a train of three and five pulses during the cooling to 28°C. MEP amplitudes were expressed as percentages of the control MEP amplitude (%MEP amplitude), which was measured at 38°C. Data are mean ± SEM. a, P < 0.05 versus 38°C; b, P < 0.05 versus three and five pulses.
|
|
The onset latencies of MEPs after a single and a train of pulses increased linearly with a reduction of esophageal temperature (Fig. 2). The latencies after a single and a train of pulses at 28°C, 30°C, and 32°C were significantly longer compared with those at 38°C (P < 0.05). The representative MEPs after a single and a train of five pulses during the cooling are shown in Figure 3.
View larger version (13K):
[in this window]
[in a new window]
|
Figure 2. The onset latencies of motor-evoked potentials (MEPs) after electrical stimulation of the motor cortex with a single pulse and a train of three and five pulses during the cooling to 28°C. Data are mean ± SEM. a, P < 0.05 versus 38°C.
|
|
View larger version (5K):
[in this window]
[in a new window]
|
Figure 3. Representative motor-evoked potentials (MEPs) after electrical stimulation of the motor cortex with a single pulse and a train of five pulses at 38°C, 32°C, and 28°C. MEP amplitude after single-pulse stimulation was decreased during the cooling, whereas MEP amplitude after train-pulse stimulation remained unchanged.
|
|
Blood concentration of propofol during the cooling is shown in Table 3. Propofol concentration was increased with a reduction of core temperature. Propofol concentration at 28°C was significantly larger compared with that at 38°C (P < 0.05).
|
Discussion
|
|---|
The results in the present study show that a reduction of core temperature to 28°C did not significantly influence amplitude of MEP to multipulse stimulation with a train of three or five pulses, whereas MEP amplitude to single-pulse stimulation was significantly decreased with a reduction of core temperature. MEP latency was increased linearly with a decrease in core temperature regardless of stimulation paradigms. These results indicate that monitoring of myogenic MEPs is feasible during the hypothermic conditions to 28°C as long as a train of pulses is used for stimulation in rabbits under propofol/ketamine/fentanyl anesthesia.
Although a number of investigators have reported the influence of hypothermia on sensory- and auditory-evoked potentials, there have been a few reports dealing the effect of hypothermia on MEPs (22–25). Oro and Highighi (22) investigated the effects of systemic hypothermia on spinal neurogenic MEPs recorded from the epidural space at L1-2 in rats anesthetized with pentobarbital. They demonstrated that amplitudes of spinal MEPs in response to single-pulse stimulation were significantly reduced with a decrease in core temperature, and no spinal MEPs were detectable at less than 28°C. Meylaerts et al. (23) investigated the influence of regional spinal cord hypothermia on myogenic MEPs in response to transcranial electrical stimulation with a train of five pulses in pigs anesthetized with ketamine, sufentanil, and nitrous oxide. Progressive cooling resulted in an increase in MEP amplitude at 28°C–30°C and was followed by a progressive decrease. In the present study, MEP amplitudes to single-pulse stimulation were significantly reduced, whereas after stimulation with a train of pulses, MEP amplitudes did not change significantly during the cooling to 28°C. Collectively, the influence of hypothermia on MEP amplitudes can vary depending on stimulation paradigms. MEPs to single-pulse stimulation may be sensitive to suppression by hypothermic conditions compared with those to train-pulse stimulation.
The reasons for this difference are unknown. However, the possible mechanisms are as follows: First, the influence of hypothermia on synaptic transmission of MEPs may differ between single-pulse and train-pulse stimulation. Synaptic transmission has been regarded as the primary site of anesthetic-mediated suppression of MEPs (7). When the descending impulses are inhibited during anesthesia, temporal accumulation of several excitatory postsynaptic potentials is required to bring motor neurons from the resting state to the firing threshold. Therefore, a train of pulses with an interstimulus interval of 2–3 ms has been used for electrical stimulation for MEPs during general anesthesia (9–11). Maylaerts et al. (23) indicated that a release of the neurotransmitter might be increased in the synaptic space because of longer duration of the action potentials during hypothermic conditions. Because increased duration of individual potentials may result in summation, MEPs to train-pulse stimulation might become hyperresponsive during hypothermia. In fact, they demonstrated that amplitudes of MEPs to train-pulse stimulation were increased with a reduction of temperature to 28°C.
Second, hypothermia-induced changes in background anesthetic concentration might have influenced the results in the present study. As the regimen of propofol administration, we used a bolus of 10 mg/kg of propofol followed by a continuous infusion of propofol at an infusion rate of 0.8 mg · kg-1 · min-1. This dosage was compatible with that in the previous study (26,27). Aeschbacher and Webb (26) reported that a mean propofol infusion rate of 0.876 mg · kg-1 · min-1 produced a light plane of anesthesia in which palpable reflex, the reaction to ear pinching, and the front and hind limb withdrawal reflex were abolished in rabbits. Ma et al. (27) measured the blood concentration of propofol when propofol was infused at a rate of 0.8 mg · kg-1 · min-1 in rabbits. They demonstrated that blood concentration of propofol remained constant. These studies suggest that an increase in propofol concentration in the present study would be mainly attributed to a reduction of core temperature. An increase in propofol concentration during the cooling should have had a suppressive influence on myogenic MEPs in the present study. In fact, %MEP amplitude after single-pulse stimulation was significantly reduced with a reduction of core temperature. Our previous study in rabbits demonstrated that MEP amplitude to single-pulse stimulation was significantly reduced with an increase of propofol, whereas the influence of propofol on MEP amplitude in response to a train-pulse stimulation was less than that to single-pulse stimulation (15). Therefore, it is not clear whether the MEP suppression observed in this study is caused by hypothermia itself or by the increase in serum propofol levels that accompanied the hypothermia. Further study would be required.
MEP latencies were linearly increased with a reduction of core temperature regardless of stimulation paradigms. These findings are compatible with those in the previous studies (22,23). Oro and Haghighi (22) demonstrated that systemic hypothermia increased early wave latency and interpeak latencies of spinal MEPs in rats. Meylaerts et al. (23) also reported that progressive subdural hypothermia progressively increased myogenic MEPs in pigs. A number of studies have also demonstrated that hypothermia prolonged the latency of sensory-, auditory-, and visual-evoked potentials (25). Although the effects of hypothermia on amplitudes of such potentials are variable, their influence on latency seems to be consistent.
In summary, we investigated the effect of hypothermia on myogenic MEPs to electrical stimulation with a single pulse and a train of pulses under propofol/ketamine/fentanyl anesthesia in rabbits. The results indicate that, although MEP latency was increased linearly with a reduction of core temperature, MEP amplitudes remained unchanged during cooling to 28°C as long as a train of pulses was used for stimulation. These results suggest that monitoring of myogenic MEPs may be feasible during hypothermic conditions to 28°C. Further study would be required to determine if MEP monitoring is feasible at less than 28°C under general anesthesia. An increase of propofol concentration during hypothermic conditions also suggested that anesthetic titration for intraoperative monitoring of myogenic MEPs may be crucial during the hypothermic conditions.
|
Acknowledgments
|
|---|
Supported, in part, by Grants in Aid for Scientific Research (10671439) in Japan.
|
References
|
|---|
- Wan ITP, Angelini GD, Bryan AJ, et al. Prevention of spinal cord ischaemia during descending thoracic and thoracoabdominal aortic surgery. Eur J Cardio-Thorac Surg 2001; 19: 203–13.[Abstract/Free Full Text]
- Jacobs MJHM, Meylaerts SA, de Haan P, et al. Strategies to prevent neurological deficit based on motor-evoked potentials in type I and II thoracoabdominal aortic aneurysm repair. J Vasc Surg 1999; 29: 48–59.[ISI][Medline]
- Kalkman CJ, Drummond JC, Ribberink AA, et al. Effect of propofol, etomidate, midazolam, and fentanyl on motor evoked responses to transcranial electrical or magnetic stimulation in humans. Anesthesiology 1992; 76: 502–9.[ISI][Medline]
- Kawaguchi M, Sakamoto T, Shimizu K, et al. Effect of thiopentone on motor evoked potentials induced by transcranial magnetic stimulation in humans. Br J Anaesth 1993; 71: 849–53.[Abstract/Free Full Text]
- Kawaguchi M, Inoue S, Kakimoto M, et al. The effect of sevoflurane on myogenic motor-evoked potentials induced by single and paired transcranial electrical stimulation of the motor cortex during nitrous oxide/ketamine/fentanyl anesthesia. J Neurosurg Anesthesiol 1998; 10: 131–6.[ISI][Medline]
- Kalkman CJ, Drummond JC, Ribberink AA. Low concentrations of isoflurane abolish motor evoked responses to transcranial electrical stimulation during nitrous oxide/opioid anesthesia in humans. Anesth Analg 1991; 73: 410–5.[Abstract/Free Full Text]
- Zentner J, Albercht T, Heuser D. Influence of halothane, enflurane, and isoflurane on motor evoked potentials. Neurosurgery 1992; 31: 298–305.[ISI][Medline]
- Zentner J, Kiss I, Ebner A. Influence of anesthesia–nitrous oxide in particular–on electromyographic response evoked by transcranial electrical stimulation of the cortex. Neurosurgery 1989; 24: 253–6.[ISI][Medline]
- Kalkman CJ, Ubags LH, Been HD, et al. Improved amplitude of myogenic motor evoked responses after paired transcranial electrical stimulation during sufentanil/nitrous oxide anesthesia. Anesthesiology 1995; 83: 270–6.[ISI][Medline]
- Taniguchi M, Cedzich C, Schramm J. Modification of cortical stimulation for motor evoked potentials under general anesthesia: technical description. Neurosurgery 1993; 32: 219–26.[ISI][Medline]
- Kawaguchi M, Sakamoto T, Ohnishi H, et al. Intraoperative myogenic motor evoked potentials induced by direct electrical stimulation of the exposed motor cortex under isoflurane and sevoflurane. Anesth Analg 1996; 82: 593–9.[Abstract]
- Kawaguchi M, Shimizu K, Furuya H, et al. Effect of isoflurane on motor-evoked potentials induced by direct electrical stimulation of the exposed motor cortex with single, double, and triple stimuli in rats. Anesthesiology 1996; 85: 1176–83.[ISI][Medline]
- Ubags LH, Kalkman CJ, Been HD. Influence of isoflurane on myogenic motor evoked potentials to single and multiple transcranial stimuli during nitrous oxide/opioid anesthesia. Neurosurgery 1998; 43: 90–5.[ISI][Medline]
- Kawaguchi M, Sakamoto T, Inoue S, et al. Small dose of propofol can be effectively used as a supplement of ketamine-based anesthesia during intraoperative monitoring of myogenic transcranial motor evoked potentials. Spine 2000; 25: 974–9.[ISI][Medline]
- Sakamoto T, Kawaguchi M, Inoue S, Furuya H. Suppressive effect of nitrous oxide on motor evoked potentials can be reversed by train stimulation in rabbits under ketamine/fentanyl anaesthesia, but not with additional propofol. Br J Anaesth 2001; 86: 395–402.[Abstract/Free Full Text]
- van Dongen EP, Schepens MA, Morshuis WJ, et al. Thoracic and thoracoabdominal aortic aneurysm repair: use of evoked potential monitoring in 118 patients. J Vasc Surg 2001; 34: 1035–40.[ISI][Medline]
- Sueda T, Morita S, Okada K, et al. Selective intercostals arterial perfusion during thoracoabdominal aortic aneurysm surgery. Ann Thorac Surg 2000; 70: 44–7.[Abstract/Free Full Text]
- de Haan P, Kalkman CJ, Jacobs MJHM. Spinal cord monitoring with myogenic motor evoked potentials: early detection of spinal cord ischemia as an integral part of spinal cord protective strategies during thoracoabdominal aneurysm surgery. Semin Thorac Cardiovasc Surg 1998; 10: 19–24.[Medline]
- Matsumoto M, Iida Y, Sakabe T, et al. Mild and moderate hypothermia provide better protection than a burst-suppression dose of thiopental against ischemic spinal cord injury in rabbits. Anesthesiology 1997; 86: 1120–7.[ISI][Medline]
- Marsala M, Vanicky I, Yaksh TL. Effect of graded hypothermia (27 degrees to 34 degrees C) on behavioral function, histopathology, and spinal blood flow after spinal ischemia in rat. Stroke 1994; 25: 2038–46.[Abstract]
- Kakinohana M, Taira Y, Marsala M. The effects of graded postischemic spinal cord hypothermia on neurological outcome and histopathology after transient spinal ischemia in rat. Anesthesiology 1999; 90: 789–98.[ISI][Medline]
- Oro J, Haghighi SS. Effect of altering core body temperature on somatosensory and motor evoked potentials in rats. Spine 1992; 17: 498–503.[ISI][Medline]
- Meylaerts SA, de Haan P, Kalkman CJ, et al. The influence of regional spinal cord hypothermia on transcranial myogenic motor-evoked potential monitoring and the efficacy of spinal cord ischemia detection. J Thorac Cardiovasc Surg 1999; 118: 1038–45.[Abstract/Free Full Text]
- Kakimoto M, Kawaguchi M, Sakamoto T, et al. Effect of nitrous oxide on myogenic motor evoked potentials during hypothermia in rabbits anaesthetized with ketamine/fentanyl/propofol. Br J Anaesth 2000; 88: 836–40.
- Jou IM. Effects of core body temperature on changes in spinal somatosensory-evoked potentials in acute spinal cord compression injury: an experimental study in the rat. Spine 2000; 25: 1878–85.[ISI][Medline]
- Aeschbacher G, Webb AI. Propofol in rabbits. II. Long-term anesthesia. Lab Anim Sci 1993; 43: 328–35.[ISI][Medline]
- Ma D, Chakrabarti MK, Whitwam JG. Effects of propofol and remifentanil on phrenic nerve activity and nociceptive cardiovascular responses in rabbits. Anesthesiology 1999; 91: 1470–80.[ISI][Medline]
Accepted for publication February 10, 2003.
This article has been cited by other articles:
|
|
|
|
 
Y. Yamamoto, M. Kawaguchi, M. Kakimoto, S. Inoue, and H. Furuya
The Effects of Dexmedetomidine on Myogenic Motor Evoked Potentials in Rabbits
Anesth. Analg.,
June 1, 2007;
104(6):
1488 - 1492.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Yamamoto, M. Kawaguchi, M. Kakimoto, M. Takahashi, S. Inoue, T. Goto, and H. Furuya
The effects of xenon on myogenic motor evoked potentials in rabbits: a comparison with propofol and isoflurane.
Anesth. Analg.,
June 1, 2006;
102(6):
1715 - 1721.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
