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(Stroke. 2002;33:1165.)
© 2002 American Heart Association, Inc.

Letters to the Editor

Re: Safety of Intraventricular Sodium Nitroprusside and Thiosulfate for the Treatment of Cerebral Vasospasm in the Intensive Care Unit Setting

Robert H. Rosenwasser, MD

Division of Cerebrovascular Surgery and Interventional Neuroradiology, Department of Neurosurgery, Thomas Jefferson University, Philadelphia, Pennsylvania

To the Editor:

I read with interest the report by Thomas and McGinnis on safety of intraventricular sodium nitroprusside for the treatment of cerebral vasospasm.¹ As Director of Cerebrovascular Surgery and Surgical Director of the Neurosurgical Intensive Care Service at Thomas Jefferson University, I had firsthand interaction with and care of every patient listed in this study. Virtually all of these patients were treated with prophylactic volume expansion and HHH (hypertensive, hypervolemic, hemodilutional) therapy, and, as reported in Table 1 of the article, several were treated with angioplasty. The conclusion that the beneficial effects were from sodium nitroprusside and thiosulfate is entirely misleading. That conclusion cannot be drawn. Many of these patients had intractable intracranial pressure, necessitating interruption of the therapy, and in patients who were awake, therapy often had to be interrupted due to intractable nausea and vomiting, even when they were premedicated with doses of Zofran, administered even in the chemotherapeutic range.

Patient 4 (seen in Figure 3A of the article), who was directly under my care, is listed as a satisfactory result. Although he walks and smiles, he is in fact neurologically and cognitively devastated and cannot even remember where the bathroom is in his own house.

Although the data are interesting, I think the conclusions drawn are very similar to a conclusion that 2+2=8. The results of the initial reports were certainly very encouraging; however, at this point I do not think any conclusions can be drawn and I would certainly not advocate a prospectively randomized trial at this point.

References

1. Thomas JE, McGinnis G. Safety of intraventricular sodium nitroprusside and thiosulfate for the treatment of cerebral vasospasm in the intensive care unit setting. Stroke. 2002; 33: 486–492.[Abstract/Free Full Text]

Jeffrey E. Thomas, MD

Neurovascular and Neurointerventional Surgery Division of Neurosurgery University of New Mexico Health Sciences Center Albuquerque, New Mexico

Response

Thank you for the opportunity to respond to the letter written by Dr Rosenwasser. I do question the reasoning behind Dr Rosenwasser’s letter, as he seems to simply reiterate the points of the article, the emphasis of which is safety and not efficacy. It is clearly stated in the article, for example, that patient received HHH therapy and, in some cases, cerebral angioplasty. It is also stated that the administration of the medication was limited by intracranial hypertension so that in almost all cases therapy could not be initiated until vasospasm was already established. It is also clearly stated that nausea and vomiting were common side effects of the therapy. The reason for reiterating these points from the article in a letter to the Editor as though they were new information is obscure.

With regard to the patient to whom Dr Rosenwasser alluded (1 of 2 treated by him in this study), the facts of the case are stated quite clearly:

1. Vasospasm sufficiently severe to produce paraplegia and diagnostic confusion (the patient was misdiagnosed with a spinal cord lesion for several days) was present for a prolonged period of time.
   
2. The patient’s vasospasm was refractory to HHH therapy, which was the reason and justification for commencing intraventricular (intrathecal) sodium nitroprusside and thiosulfate (ITSNP/T) therapy. Most importantly, US Food and Drug Administration approval of this protocol under Investigational New Drug Protocol 52-307 (Jeffrey E. Thomas, MD) was the basis for initial Institutional Review Board approval at Thomas Jefferson University (#97.9035), which initially required that the protocol be instituted only for medically refractory vasospasm. Therefore, Dr Rosenwasser’s assertion that neurological improvement resulted from volume expansion and HHH therapy is illogical. Had this been the case, ITSNP/T therapy would not have been indicated and Dr Rosenwasser presumably would not have suggested it for his own patient.
   
3. The patient began to move his legs, for the first time in several days, within 1 hour of receiving medication and recovered to full ambulatory status.
   
4. The patient’s neurological improvement coincided exactly with a profound drop in transcranial Doppler ultrasonography velocities (mean 200 to 60 cm/sec within 60 minutes) as demonstrated in the accompanying table (Figure 3). Although it is possible that the patient’s abrupt neurological improvement occurred coincidentally with the administration of medication, it does not seem likely.
   
5. A short-term memory deficit in a patient with severe prolonged vasospasm in the anterior cerebral artery distribution following rupture of an aneurysm of the anterior communicating artery is certainly not inconsistent with the aftermath of perihypothalamic subarachnoid hemorrhage and cerebral vasospasm. Because the patient presented with paraplegia and severe mental status abnormality, it is not reasonable to assume that this residual memory deficit was somehow caused by the medication when all other clinical responses demonstrated a beneficial effect. This is especially true in view of the clinical responses of other patients, both in this study and in others.^1–5 Since this patient’s vasospasm was clearly refractory to aggressive HHH therapy, it is more reasonable to assume that his outcome might have been worse without this intervention, although this is most certainly not a conclusion of the article. Finally the patient’s memory deficit is specifically and accurately noted in the text, Figure 3, and Table 2, and therefore Dr Rosenwasser’s statement that this patient is ‘listed as a satisfactory result‘ is also grossly erroneous.
   

A most important point of this study that seems to also have been misinterpreted by Dr Rosenwasser is that this is a safety study. This should be clear to anyone reading the title of the article. Although clinical outcomes of patients treated in this manner with ITSNP/T have generally been good and some angiographic,³ laboratory,⁶ and neurological^1–4 results have been dramatic, no claim to efficacy of this treatment for cerebral ischemia due to vasospasm has ever been made in this or in other articles. Studies by other investigators have been similarly viewed with caution^5,7 (see reviews). Because preliminary investigations by other investigators^2,5 have indeed demonstrated beneficial effects pertaining to enhanced cerebral oxygenation and cerebral blood flow, and because we and others have indeed observed good clinical results with this treatment, we believe that a prospective randomized multi-institutional trial of ITSNP/T is justified and advisable. Since the only way to find out whether this new treatment has true therapeutic value is to perform such a study, the suggestion that it should not be performed, in the absence of evidence of unacceptable risk, is both illogical and contradictory.³

References

1. Thomas JE, McGinnis G. Safety on intraventricular sodium nitroprusside and thiosulfate for the treatment of cerebral vasospasm in the intensive care unit setting. Stroke. 2002; 33: 486–492.
2. Vajkoczy P, Hubner U, Horn P, Bauhauf C, Thome C, Schilling L, Schmiedek P, Quintel M. Intrathecal sodium nitroprusside improves cerebral blood flow and oxygenation in refractory cerebral vasospasm and ischemia in humans. Stroke. 2000; 31: 1195–1197.Letter.
3. 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.[Abstract/Free Full Text]
4. Thomas JE, Rosenwasser RH. Reversal of severe cerebral vasospasm in three patients after aneurysmal subarachnoid hemorrhage: initial observations regarding the use of intraventricular sodium nitroprusside in humans. Neurosurgery. 1999; 44: 48–57.[CrossRef][Medline] [Order article via Infotrieve]
5. Raabe A, Zimmerman M, Setzer M, Vatter H, Berkefeld J, Seifert V. The effect of intraventricular sodium nitroprusside on cerebral hemodynamics and oxygenation in poor-grade aneurysm patients with severe, medically refractory vasospasm. Neurosurgery. In press.
6. Thomas JE, Nemirovsky A, Zelman V, Giannotta SL. Rapid reversal of endothelin-1-induced cerebral vasoconstriction by intrathecal administration of nitric oxide donors. Neurosurgery. 1997; 40: 1245–1249.[CrossRef][Medline] [Order article via Infotrieve]
7. Thomas J. Intrathecal sodium nitroprusside improves cerebral blood flow and oxygenation in refractory cerebral vasospasm and ischemia in humans. Stroke. 2000; 31: 1196–1197.Letter response.

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