(Stroke. 2000;31:1194-b.)
© 2000 American Heart Association, Inc.
Letters to the Editor |
Intrathecal Sodium Nitroprusside Improves Cerebral Blood Flow and Oxygenation in Refractory Cerebral Vasospasm and Ischemia in Humans
Department of Neurosurgery
Department of Anesthesiology, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany
To the Editor:
With great interest we read the article by Thomas et al1 recently published in Stroke. The authors proposed the intrathecal administration of the nitric oxide donor sodium nitroprusside (SNP) as a novel means to treat refractory cerebral vasospasm. However, although amelioration or even reversal of large cerebral vessel constriction was shown by cerebral angiography, the article failed to provide data on the acute and long-term effect of SNP on cerebral vasospasm–associated ischemia and hypoxia. Therefore, in addition to their report, we here show the effect of intrathecal SNP on episodes of severely reduced cerebral blood flow and brain tissue oxygenation in a patient suffering from refractory cerebral vasospasm.
Seven days after subarachnoid hemorrhage (Hunt and Hess grade II) and uneventful operation of bilateral middle cerebral artery (MCA) aneurysms, a 31-year-old female patient presented with right-sided hemiparesis and progressive neurological deterioration. Transcranial Doppler recordings of the MCAs had elevated from values <100 cm/s to 205 cm/s and 180 cm/s on the left and right sides, respectively. Cerebral angiography revealed severe cerebral vasospasm, which was most pronounced in the left MCA (M1 and M2 segments). Consequently, the patient was sedated and intubated, and a right frontal ventriculostomy for intracranial pressure (ICP) monitoring was performed. In addition, a polarographic brain tissue oxygen (ptiO2) microprobe2 and a thermal diffusion regional cerebral blood flow (rCBF) microprobe3 were implanted subcortically into the white matter of the left frontal MCA territory. Thereby, using a PC-based multimodality neuromonitoring system, mean arterial blood pressure (MABP), ICP, cerebral perfusion pressure (CPP=MABP-ICP), ptiO2, and rCBF were monitored continuously at the bedside with a sampling rate of 1 Hz. Thresholds for severe ischemia and hypoxia were defined as rCBF <6 mL/100 g/min and ptiO2 <10 mm Hg, as previously reported.3 4
Following the diagnosis of cerebral vasospasm, selective
intra-arterial administration of papaverin (300 mg),
hypertensive/hypervolemic/hemodilutional (HHH) therapy, and
increasing the inspired fraction of oxygen to >70% were initially
successful in controlling cerebral ischemia and hypoxia
(Table
). When HHH therapy,
however, had to be discontinued due to cardial decompensation of the
patient, rCBF and ptiO2 dropped again to severe
ischemic and hypoxic values (Table). As a last measure, SNP was
delivered intraventricularly via the
ventriculostomy, as previously described1 (4 mg/mL,
dissolved in the patient’s cerebrospinal fluid). Dosing of SNP was
intermittent and adjusted to changes in rCBF and ptiO2.
Despite a modest reduction in CPP, rCBF and ptiO2 rapidly
increased 4-fold and 7.5-fold, respectively, within 30 minutes after
delivery of 20 mg SNP (Table). Because this effect was only transient
and all parameters had returned to baseline 3 hours after
treatment, an additional 16 mg of SNP was administered. Similar to the
first SNP administration, rCBF and ptiO2 values rapidly
improved again within 30 minutes after delivery (Table). The second SNP
administration, however, resulted in a permanent reversal of severe
cerebral ischemia and hypoxia, eventually achieving
moderate clinical recovery of the patient.
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In the present report we demonstrate for the first time that the intrathecal administration of the nitric oxide donor SNP is effective in improving cerebral blood flow and oxygenation in otherwise refractory cerebral vasospasm in humans. The potentially temporary efficacy and possible adverse effects on CPP and ICP, however, warrant a continuous bedside multimodality neuromonitoring of hemodynamic parameters, cerebral blood flow and brain tissue oxygenation during SNP therapy.
This study was supported by the German Research Foundation (VA 151/5-1)
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References
1.
Thomas JE, Rosenwasser RH, Armonda RA, Harrop J,
Mitchell W, Galaria I. Safety of intrathecal sodium
nitroprusside for the treatment and prevention of refractory cerebral
vasospasm and ischemia in humans. Stroke.. 1999;30:1409–1416.
2. Kiening KL, Unterberg AW, Bardt TF, Schneider GH, Lanksch WR. Monitoring of cerebral oxygenation in patients with severe head injuries: brain tissue PO2 versus jugular vein oxygen saturation. J Neurosurg.. 1996;85:751–757.[Medline] [Order article via Infotrieve]
3. Thome C, Vajkoczy P, Horn P, Roth H, Huebner U, Luecke T, Zapletal C, Klar E, Schilling L, Schmiedek P. Validation and clinical application of a novel intraparenchymal microprobe for the continuous monitoring of regional cerebral blood flow. J Cereb Blood Flow Metab.. 1999;19:S623. Abstract.
4.
Kaufmann AM, Firlik AD, Fukui MB, Wechsler LR, Jungries
CA, Yonas H. Ischemic core and penumbra in human stroke.
Stroke.. 1999;30:93–99.
Response
Division of Cerebrovascular Surgery and Interventional Neuroradiology,, Department of Neurological Surgery, Thomas Jefferson University and Wills Neurosensory Institute, Philadelphia, Pennsylvania
Key Words: nitricloxide • vasospasm • cerebral aneurysm
Dr Vajkoczy and colleagues present an intriguing observation
that appears to have been beneficial to the patient. Although we are
cautious in interpreting these limited experiences in terms of
efficacy, these results corroborate our clinical experience with
intrathecal SNP in several ways. (1) As illustrated
in our recent articleR1 referenced by these authors,
improvement in CBF was suggested by acceleration of cerebral
circulation time at the same MABP and ICP. This sometimes occurred
without a dramatic change in the caliber of cerebral conductance
vessels and was interpreted by us as evidence of dilated collateral
circulation below the level of angiographic resolution. The same
inference, ie, increased regional cerebral blood flow, applies to the
enhanced angiographic blush observed in treated patients (Figure 1
). (2) MAB remained relatively stable,
and ICP remained within normal range. (3) The improvement in measured
parameters was accompanied by clinical improvement,
suggesting minimal or no neurotoxicity. Indeed our most recent
experience with treating patients by this method in the intensive care
unit without angiography has been noteworthy for several episodes of
profound and rapid neurological improvement within several hours of
treatment, sometimes without a clear relationship to the vessels deemed
constricted by transcranial Doppler (J. Thomas
et al, unpublished observations). Such observations also suggest
an effect at the level of collateral circulation. (4) The effect of the
first treatment by these authors was transient, and vasospasm returned,
supporting the hypothesis that it is indeed a substrate-dependent
phenomenon that is liable to recur until the substrate
(oxyhemoglobinR1 ) is exhausted.R2
It is also interesting that the reported patient was initially treated with intra-arterial papaverine, the effect of which was not lasting. This has also been our experience with papaverine.
Finally, a caveat regarding conclusions drawn from relatively few
patients is in order. Our purpose in the referenced article was to
emphasize the apparent safety of intrathecal SNP in initial
trials, and not its efficacy. It does appear that the treatment may be
efficacious in some patients, even dramatically so, but we have seen
two patients whose established vasospasm has not responded to this
treatment, and the reasons for this are still unclear. Several points
are worth mentioning in this regard. (1) Dosage must be scrupulously
controlled to avoid hypotension, but nitric oxide may be rapidly
absorbed by the hemoglobin in the subarachnoid clot, thereby
making elevated dosage not only possible but necessary. This problem of
a hemoglobin "sink" might theoretically be aggravated by
intraventricular hemorrhage if the
preparation is being administered
intraventricularly. (2) The relatively slow rate of
infusion of very small volumes of SNP makes photo-inactivation of the
compound a very serious threat. For this reason even the smallest gap
in light protection (foil wrap) must be avoided. This risk cannot be
overemphasized. (3) It has been our experience that if vasospasm
severity exceeds a certain threshold, it may be impossible to reverse
with this treatment. For this reason we begin treatment very
early, preferably as soon as the aneurysm is secured for a
patient at high risk for vasospasm, and upon obtaining any evidence of
impaired cerebral circulation, such as transcranial
Doppler or cerebral blood flow or oximetry, even when the patient
remains neurologically stable. (4) As mentioned in our article,
intracranial pressure problems may make treatment by this method
untenable, at least in the short term, if not definitively. Thus severe
vasospasm may become established. Such patients should be considered
early for balloon angioplasty if possible, despite its restriction to
the larger vessels. (5) Treatment may be hindered by nausea and
vomiting, which seems to be a problem only in fully awake patients.
High-dose ondansetron-HCl, which works synergistically with
dexamethasone (3), is very helpful in this regard. (6)
Since ventriculostomy is a "blind" neurosurgical procedure,
attention must be given to correct intraventricular
catheterization before treatment is begun. CT should be
obtained initially, but safety is ultimately determined by the facile
withdrawal of cerebrospinal fluid from the catheter just prior to
treatment. Although an intraparenchymal injection of 1.0 mL may not be
harmful in a patient without intracranial hypertension (see Figure 2), such a patient may have no benefit
from the treatment administered extra-ventricularly. (7)
The role of cerebrospinal fluid circulation in the successful
administration of intrathecal sodium nitroprusside remains
uncertain. Such circulation is obviously impaired in many patients with
high-grade aneurysmal subarachnoid
hemorrhage.
We applaud the authors for their meticulous and successful care of their patient, and for their careful and encouraging measurements of treatment effect. We emphasize, however, that the true efficacy of this treatment remains unknown, and only through a methodical prospective analysis can its value be determined. We look forward to reporting the results of our prospective study in the very near future.
References
1. Thomas JE, Rosenwasser RH, Armonda RA, Harrop J, Mitchell W, Galaria I. Safety of intrathecal sodium nitroprusside for the treatment and prevention of refractory cerebral vasospasm and ischemia in humans. Stroke.. 1999;30:1409–1416.
2.
Barrows LJ, Hunter FT, Banker BQ. The nature and
clinical significance of pigments in the cerebrospinal fluid.
Brain.. 1955;78:59–80.
3. Gralla RJ. Antiemetic therapy. Sem. Oncol.. 1998;25:577–583.[Medline] [Order article via Infotrieve]
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