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Ann Thorac Surg 1996;61:113-117
© 1996 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Effect of Nitroglycerin on Spinal Cord Ischemia After Thoracic Aortic Cross-Clamping

Department of Anesthesiology, Long Island Jewish Medical Center, New Hyde Park, New York

Accepted for publication August 28, 1995.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Background. Thoracic aortic cross-clamping with the use of sodium nitroprusside (SNP) has been shown to cause a decrease in spinal cord perfusion pressure and an increased incidence of paraplegia. Nitroglycerin is frequently used in this setting. This study investigated the effects of nitroglycerin and SNP on spinal cord ischemia.

Methods. Three groups of 8 mongrel dogs underwent thoracic aortic cross-clamping for 45 minutes. Proximal pressure was maintained between 95 and 100 mm Hg with SNP, nitroglycerin, or phlebotomy. All animals were neurologically evaluated 24 hours later by a blinded observer, and the findings were confirmed by histopathologic study. Statistical analysis (p value of less than 0.05) of measured hemodynamic data was by analysis of variance and of Tarlov scores, the Mann-Whitney U test.

Results. Distal aortic pressures (p < 0.001), Tarlov scores, and spinal cord perfusion pressures (p < 0.01 and p < 0.05 for SNP group and nitroglycerin group, respectively) were significantly higher in the phlebotomy group compared with the SNP and NTG groups. Cerebrospinal fluid pressures were significantly lower in the phlebotomy group compared with the SNP group (p < 0.001).

Conclusions. The use of either NTG or SNP was associated with a high incidence of paraplegia. Nitroglycerin appears to be no safer than SNP when used during thoracic aortic cross-clamping.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
The management of patients undergoing a thoracic aortic operation is a challenge for both the anesthesiologist and the surgeon. The hemodynamic changes caused by the application of the thoracic aortic cross-clamp are substantial 1] and include proximal hypertension, increased myocardial wall stress, and decreased cardiac output. Spinal cord ischemia and paraplegia continues to occur after thoracic aortic cross-clamping and can be a devastating complication of thoracic aortic procedures. Despite the various techniques that have been used in an attempt to prevent spinal cord ischemia, the incidence of paraplegia remains high at 3% to 38% [2, 3].

Of the many agents used to control the proximal hypertension associated with thoracic aortic cross-clamping [4–6], sodium nitroprusside (SNP) has been a mainstay [4]. Our group [7], Marini and associates [8], and Cernaianu and co-workers [9] have all demonstrated in a canine model that SNP, when used to control proximal pressure during thoracic aortic cross-clamping, worsens both spinal cord perfusion pressure and neurologic outcome.

Nitroglycerin (NTG), another vasodilator, has been used both alone [10] and in conjunction with SNP [4] to control proximal pressure in aortic operations. It offers the potential benefit of myocardial protection because of its effects on preload, myocardial wall stress, myocardial compliance, and improved myocardial oxygen supply to demand ratio [4].

Although NTG can increase intracranial pressure in a setting of decreased intracranial compliance, its effect on spinal cord perfusion pressure and spinal cord ischemia in the setting of thoracic aortic cross-clamping is unknown. The present study was designed to compare the effects of NTG and SNP on spinal cord ischemia when these agents are used to control proximal hypertension during thoracic aortic cross-clamping.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
This study was approved by the institutional animal use committee. All animals received humane care in compliance with the ``Guide for the Care and Use of Laboratory Animals'' published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Animal Study
A total of 24 adult mongrel dogs were used in this study. All animals weighed between 15 and 24 kg and were fasted for 12 hours prior to the procedure. The dogs were anesthetized with intravenous administration of sodium pentobarbital (35 to 40 mg/kg), tracheally intubated, and given fentanyl (15 µg/kg), pancuronium bromide (0.1 to 0.15 mg/kg), and gentamicin sulfate (1 mg/kg). Their lungs were ventilated with 100% oxygen, with the arterial carbon dioxide tension maintained at 25 to 30 mm Hg as confirmed by end-tidal carbon dioxide as well as arterial blood gas analysis. All animals were placed on a warming blanket, and rectal temperature was maintained at 36° to 37°C. The electrocardiogram was continuously recorded using needle electrodes.

Under sterile conditions, right femoral artery (distal arterial pressure), right external jugular vein, and right carotid artery (proximal arterial pressure) catheters were placed by cutdown for continuous pressure monitoring. In all dogs, a 22-gauge cisterna cerebellomedullaris subarachnoid needle was placed for continuous cerebrospinal fluid (CSF) pressure measurement. A multigas analyzer (Datex, Helsinki, Finland) was used to measure end-tidal carbon dioxide concentration. Cerebrospinal fluid and proximal and distal systolic, diastolic, and mean pressure measurements were continuously obtained using disposable transducers (Abbott Laboratories, North Chicago, IL) with pressure amplifiers (Gould, Inc, Cleveland, OH), and recorded on a continuous recorder (Gould, Inc). All data were also recorded with a computer-driven continuous data-acquisition program (Gould, Inc).

The 24 dogs were randomly assigned to one of three groups distinguished by the method of controlling proximal hypertension. In 8 animals, this was accomplished with SNP; in 8 more, with NTG; and in 8, with phlebotomy. The amount of blood removed in the phlebotomy group ranged from 30 to 45 mL/kg. The dose of SNP or NTG was in the range of 25 to 45 µg•kg^-1•min^-1.

Dogs are known to be resistant to SNP and NTG. Therefore, to decrease the vasodilator requirement and to aid in resuscitation after removal of the cross-clamp, blood (7 mL/kg) was drained into a citrate collection bag to be returned during subsequent resuscitation. Under sterile conditions, a left thoracotomy was performed, and the descending thoracic aorta was cross-clamped 1 cm distal to the takeoff of the left subclavian artery for 45 minutes.

In all three groups, proximal blood pressure was maintained at 95 to 100 mm Hg throughout the cross-clamp period, and distal arterial pressure was allowed to drift. Cerebrospinal fluid pressures and proximal and distal systolic, diastolic, and mean pressures as well as heart rate, oxygen saturation, and temperature were measured and recorded every minute throughout the cross-clamp period and for several minutes thereafter. Maximum possible spinal cord perfusion pressure was calculated as mean distal arterial pressure minus CSF pressure. Serum glucose levels were measured prior to, during, and immediately after aortic cross-clamping.

After 45 minutes of thoracic aortic cross-clamping, the continuous infusion of SNP or NTG was discontinued, and the cross-clamp was removed. All animals were fully resuscitated with intravenous fluids and the reinfusion of all autologous blood (including the blood removed in the phlebotomy group to control proximal blood pressure). Sodium bicarbonate and phenylephrine hydrochloride, ephedrine hydrochloride, or both were used to restore acid-base status and blood pressure.

The thoracotomy incision was closed, and intercostal blocks with 0.25% bupivacaine hydrochloride were placed. The muscle relaxant was reversed, and when the dog was breathing spontaneously, the trachea was extubated. Intravenous access was maintained, and all dogs received gentamicin (1 mg/kg) postoperatively. Twenty-four hours later, all dogs were neurologically evaluated using Tarlov's scale [11] by an observer blinded to treatment group. Tarlov's scale of neurologic injury is as follows:

• Grade 0 = spastic paraplegia and no movement of the lower limbs
  
• Grade 1 = spastic paraplegia and slight movement of the lower limbs
  
• Grade 2 = good movement of the lower limbs but unable to stand
  
• Grade 3 = able to stand but unable to walk normally
  
• Grade 4 = complete recovery
  

After the 24-hour neurologic evaluation, each dog was reanesthetized with pentobarbital, tracheally intubated, and mechanically ventilated. The thoracotomy incision was reopened, and the left ventricle was cannulated with a 14-gauge catheter. The right atrial appendage was opened, and 10% formalin was infused into the left ventricle until clear fluid appeared in the right atrium. Sections of cervical, thoracic, and lumbar spinal cord were removed for histopathologic examination and evaluated by a veterinary neuropathologist blinded to treatment group. Examination was by hematoxylin and eosin staining and light microscopy.

Statistical Analysis
Statistical analysis of measured hemodynamic data and glucose values was performed by analysis of variance for a repeated-measures model. Tarlov scores of neurologic injury and histopathologic results were analyzed with the Mann-Whitney U test. Differences were considered significant at a p value of less than 0.05. All hemodynamic data are expressed as the mean ± one standard deviation.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
There was no difference in mean proximal arterial pressure between any of the three treatment groups (Fig 1A). Further, there was no significant difference between any of the groups with respect to resuscitative drugs and serum glucose levels.

View larger version (31K): [in this window] [in a new window]   Fig 1. . (A) Mean proximal arterial blood pressures measured every minute in ascending aorta by way of right carotid artery (shown at 5-minute intervals). (B) Mean distal arterial blood pressures measured every minute in abdominal aorta (shown at 5-minute intervals). The difference between the phlebotomy group and either of the other two groups was significant (p < 0.001 [*]). (C) Cerebrospinal fluid pressure measured at 1-minute intervals in cisterna cerebellomedullaris with a 22-gauge spinal needle (shown at 5-minute intervals). The differences between the phlebotomy group and the nitroprusside group was significant (p < 0.001 [*]). (D) Spinal cord perfusion pressures calculated as mean distal blood pressure minus cerebrospinal fluid pressure at 1-minute intervals (shown at 5-minute intervals). The differences between the phlebotomy group and the other two groups were significant (p < 0.0001 versus nitroprusside group and p < 0.001 versus nitroglycerin group [*]).

Spinal cord perfusion pressure was consistently negative in the SNP and NTG groups yet consistently positive in the phlebotomy group (Fig 1D). These differences in spinal cord perfusion pressure were significant when the phlebotomy group was compared with both the SNP group (p < 0.0001) and the NTG group (p < 0.001). There was no significant difference in spinal cord perfusion pressure between the SNP and NTG groups.

Neurologic outcome (Tarlov score) was significantly better in the phlebotomy group compared with both the SNP group (p < 0.01) and the NTG group (p < 0.05). Seven of 8 SNP dogs and 6 of 8 NTG dogs sustained severe neurologic injury (Tarlov 0 or 1) whereas 7 of 8 phlebotomy dogs demonstrated no neurologic injury (Tarlov 4) (Fig 2). There was no difference in neurologic outcome between the SNP and NTG groups.

View larger version (13K): [in this window] [in a new window]   Fig 2. . Tarlov scores of neurologic injury measured 24 hours after aortic cross-clamp release. Differences were significantly different (*) between the phlebotomy and sodium nitroprusside groups (p < 0.01) and between the phlebotomy and nitroglycerin groups (p < 0.05).

View larger version (128K): [in this window] [in a new window]   Fig 3. . Photomicrograph of segment of anterior lumbar spinal cord from 1 dog treated with sodium nitroprusside. Note the pale, faded necrotic neuron (arrow) and normal neuron just next to it (arrowhead).

View larger version (131K): [in this window] [in a new window]   Fig 4. . Photomicrograph of segment of anterior lumbar spinal cord from 1 dog treated with sodium nitroprusside. Note the pale necrotic neuron in the center with a faded nucleus (arrow). Note also the swollen axon (arrowhead) on the left.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment References

In addition to marked proximal aortic hypertension, cross-clamping of the thoracic aorta results in decreased distal aortic pressure, increased CSF pressure [13], and decreased spinal cord perfusion pressure (approximated as mean distal aortic pressure - CSF pressure). A common agent used to control proximal hypertension caused by thoracic aortic cross-clamping is SNP. Recently, however, various groups [7, 9] have shown that SNP can in fact, worsen neurologic outcome when used in this setting. Nitroprusside, when used to control proximal hypertension during thoracic aortic cross-clamping, causes a further decrease in distal aortic pressure and a further increase in CSF pressure, thus further decreasing spinal cord perfusion pressure.

The present study demonstrates that NTG, when administered to control proximal hypertension associated with thoracic aortic cross-clamping, incurs the same increased risk of spinal cord ischemia as does the use of SNP. Like SNP, NTG further decreased mean distal aortic pressure and further increased CSF pressure, thereby further decreasing spinal cord perfusion pressure. This was in sharp contrast to the findings in the phlebotomy group. Thus, perhaps the mechanism of NTG- and SNP-induced spinal cord ischemia is the markedly negative spinal cord perfusion pressure that they produce.

Other possible mechanisms may explain the higher incidence of paraplegia seen in the SNP and NTG groups compared with the phlebotomy group. Both SNP and NTG cause release of nitric oxide. In fact, release of nitric oxide is their major mechanism of vasodilative action [14]. Nitric oxide, however, has also been shown to play a role in excitatory amino acid-induced neurologic injury in the setting of ischemia [15–17]. Cerebral and spinal cord ischemia can result in excessive excitatory amino acid neurotransmitter release [18, 19]. Glutamate and aspartate are two excitatory amino acid neurotransmitters that bind to subclasses of excitatory amino acid receptors, including the N-methyl-D-aspartate receptor. When stimulated by these excitatory amino acid neurotransmitters, the N-methyl-D-aspartate receptor opens nonselective divalent and monovalent cation channels allowing for the influx of Ca²⁺ and Na⁺ and the efflux of K⁺ from the neuron. Nitric oxide increases the activity of this receptor [15] and has been shown in vitro to increase N-methyl-D-aspartate-mediated neurotoxicity [20].

Another possible mechanism for the increased incidence of paraplegia seen in both the SNP and NTG groups is the potential for a steal phenomenon, that is, shunting of blood away from ischemic neural tissue as a result of the profound vasodilatation induced by SNP or NTG.

Although both SNP and NTG act as vasodilators, their primary site of action is very different. Nitroprusside exerts its effect primarily as an arterial vasodilator, thereby markedly decreasing afterload. Nitroglycerin, on the other hand, acts primarily as a venodilator, thus increasing capacitance and decreasing preload. The purpose of the phlebotomy group to serve as a control was to better simulate this decrease in preload and to nonpharmacologically control proximal hypertension seen with thoracic aortic cross-clamping. Both the phlebotomy and NTG groups had decreased preload, but the effect of the two methods on neurologic outcome was very different. Again this may be due to the better spinal cord perfusion pressure, the absence of nitric oxide release, or the potential absence of a vasodilator-mediated steal phenomenon in the phlebotomy group.

There are several limitations to the present study. First, the study was not double blinded. Nitroglycerin and SNP in solution physically look different (that is, color) from each other. In addition, phlebotomy is obviously very different from vasodilator infusion. Nevertheless, both the neurologic evaluation (Tarlov score) and the histopathologic examination were done in a blinded fashion. Second, this is a canine model, and extrapolation to the human setting may not necessarily be valid. The anatomy of the blood supply to the canine spinal cord is not the same as that of humans. However, with this model, we have demonstrated that the use of either NTG or SNP is associated with a higher incidence of neurologic injury.

In summary, the present study demonstrates that in regard to the incidence of spinal cord ischemia, NTG is not different from SNP when used to control proximal hypertension during thoracic aortic cross-clamping.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 
Address reprint requests to Dr Simpson, Department of Anesthesiology, Long Island Jewish Medical Center, 270-05 76th Ave, New Hyde Park, NY 11042.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment References

 

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