Intrathecal Sodium Nitroprusside Improves Cerebral Blood Flow and Oxygenation in Refractory Cerebral Vasospasm and Ischemia in Humans
2000; Lippincott Williams & Wilkins; Volume: 31; Issue: 5 Linguagem: Inglês
10.1161/01.str.31.5.1194-b
ISSN1524-4628
AutoresPeter Vajkoczy, Ulrich Hübner, Péter Horn, Christian Bauhuf, Claudius Thomé, Lothar Schilling, Peter Schmiedek, Michael Quintel,
Tópico(s)Lanthanide and Transition Metal Complexes
ResumoHomeStrokeVol. 31, No. 5Intrathecal Sodium Nitroprusside Improves Cerebral Blood Flow and Oxygenation in Refractory Cerebral Vasospasm and Ischemia in Humans Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessOtherPDF/EPUBIntrathecal Sodium Nitroprusside Improves Cerebral Blood Flow and Oxygenation in Refractory Cerebral Vasospasm and Ischemia in Humans Peter Vajkoczy, Ulrich Hubner, Peter Horn, Christian Bauhuf, Claudius Thome, Lothar Schilling and Peter Schmiedek Michael Quintel Peter VajkoczyPeter Vajkoczy Department of Neurosurgery , Ulrich HubnerUlrich Hubner Department of Neurosurgery , Peter HornPeter Horn Department of Neurosurgery , Christian BauhufChristian Bauhuf Department of Neurosurgery , Claudius ThomeClaudius Thome Department of Neurosurgery , Lothar SchillingLothar Schilling Department of Neurosurgery and Peter SchmiedekPeter Schmiedek Department of Neurosurgery Michael QuintelMichael Quintel Department of Anesthesiology, Klinikum Mannheim, University of Heidelberg, Mannheim, Germany Originally published1 May 2000https://doi.org/10.1161/01.STR.31.5.1194-bStroke. 2000;31:1194–1198To 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 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.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)Download figureDownload PowerPoint Figure 1. Left ICA AP cerebral angiogram of a 40-year-old man presenting with delayed neurological deficit after aneurysmal subarachnoid hemorrhage. The patient developed dysphasia and right hemiparesis. The most pronounced angiographic effect was not dramatic dilation of constricted large conductance vessels, but of small collaterals resulting in enhanced angiographic blush (arrows) and decreased cerebral circulation time (indicated in figure). Blood pressure and ICP were unaffected by treatment. A, before treatment; B, immediately after treatment. Several additional treatments were required in the intensive care unit over several days. The patient made a full neurological recovery and has returned to work as a computer systems analyst.Download figureDownload PowerPoint Figure 2. Electron microscopic appearance of rat cerebral cortex 7 days after intraparenchymal and intraventricular administration of SNP in concentration identical to that in human patients (4.0 mg/mL). The ultrastructural architecture is preserved; synaptic vesicle and cell membranes are intact (Erol Veznedaroglu, MD, unpublished data). Magnification ×30 000. Table 1. Multimodality Neuromonitoring During Intrathecal Treatment With SNPMABP, mm HgICP, mm HgCPP, mm HgrCBF, mL/100 g/minptiO2, mm HgDuring HHH therapy141161251110Before delivery of 20 mg SNP*11115963230 min after 20 mg SNP ICV102218212153 h after 20 mg SNP ICV†10713944830 min after additional 16 mg SNP ICV971285101724 h after additional 16 mg SNP ICV103158891948 h after additional 16 mg SNP ICV10623831723All parameters were sampled continuously at the bedside at 1 Hz. For each time point represented, the values were averaged over 50 seconds. Severe ischemia and hypoxia were defined as rCBF <6 mL/100 g/min and ptiO2 <10 mm Hg.4,5 ICV indicates intracerebroventricular administration.*After discontinuation of HHH therapy; †prior delivery of additional 16 mg SNP. 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.CrossrefMedlineGoogle Scholar2 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.CrossrefMedlineGoogle Scholar3 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.Google Scholar4 Kaufmann AM, Firlik AD, Fukui MB, Wechsler LR, Jungries CA, Yonas H. Ischemic core and penumbra in human stroke. Stroke..1999; 30:93–99.CrossrefMedlineGoogle ScholarstrokeahaStrokeStrokeStroke0039-24991524-4628Lippincott Williams & WilkinsResponseThomas Jeffrey E., MD052000nitricloxidevasospasmcerebral aneurysmDr 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.R2It 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. eLetters(0) eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate. Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page. Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ehlert A, Manthei G, Hesselmann V, Mathias K, Bein B and Pluta R (2016) A Case of Hyperacute Onset of Vasospasm After Aneurysmal Subarachnoid Hemorrhage and Refractory Vasospasm Treated with Intravenous and Intraventricular Nitric Oxide: A Mini Review, World Neurosurgery, 10.1016/j.wneu.2016.04.047, 91, (673.e11-673.e18), Online publication date: 1-Jul-2016. Pluta R, Bacher J, Skopets B and Hoffmann V (2016) A Nonhuman Primate Model of Delayed Cerebral Vasospasm After Aneurismal Subarachnoid Hemorrhage Experimental Neurosurgery in Animal Models, 10.1007/978-1-4939-3730-1_16, (227-250), . Pluta R, Bacher J, Skopets B and Hoffmann V (2014) A Non-Human Primate Model of Aneurismal Subarachnoid Hemorrhage (SAH), Translational Stroke Research, 10.1007/s12975-014-0371-9, 5:6, (681-691), Online publication date: 1-Dec-2014. 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May 2000Vol 31, Issue 5 Advertisement Article Information Metrics Copyright © 2000 by American Heart Associationhttps://doi.org/10.1161/01.STR.31.5.1194-b Originally publishedMay 1, 2000 PDF download Advertisement
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