Intraventricular sodium nitroprusside therapy: A future promise for refractory subarachnoid hemorrhage-induced vasospasm
A prospective study was carried out to evaluate the efficacy of intraventricular sodium nitroprousside (SNP) in the reversal of refractory vasospasm secondary to aneurysmal subarachnoid hemorrhage (SAH). Ten patients of aneurysmal SAH with symptomatic vasospasm, corroborated on Transcranial Doppler (TCD) and/or angiography, were included in the study. The mean age distribution of the patients was 50.8 years (range 33-65 years) with an equal number of males and females. Once vasospasm was refractory even after 12 hours of SAH therapy, intraventricular SNP was instilled in an escalating dose and the reversal of vasospasm was monitored on TCD and/or angiography. All patients showed improvement in TCD velocity on day 0 through day 3. Partial to complete reversal of vasospasm was demonstrated on angiography in all the patients, though not in all the vessels. Two patients who had weakness of limbs due to vasospasm improved following intraventricular SNP therapy. Vomiting was the commonest adverse effect (7/10). Three patients had mild fluctuation in blood pressure. The overall outcome was good in 6 out of 10 patients. The study suggests that intraventricular SNP therapy is effective in reversing the changes even in established cases of SAH-induced vasospasm.
Aneurysmal subarachnoid haemorrhage (SAH) is a common cause of intracranial vasospasm. Delayed cerebral ischemia due to vasospasm is a major cause of death and disability in these patients.,,, Dorsch (1995) reviewed 222 published reports on 31050 patients of SAH and found that the overall incidence of cerebral vasospasm was 67.3%. Transcranial Doppler (TCD) and angiography are the two main tools for the diagnosis of vasospasm., Various treatment options for vasospasm, for example calcium channel blockers, HHH therapy, balloon angioplasty,, and papaverine infusion have their own limitations. Lately, the role of nitric oxide (NO) in vasospasm and the use of nitric oxide donors for the therapy of vasospasm have raised hopes for its future management.,,
A prospective study was carried out to evaluate the efficacy of nitric oxide donor (SNP) in the reversal of aneurysmal SAH-induced cerebral vasospasm in clinically symptomatic cases under careful monitoring by TCD, cerebral angiogrpahy and clinical evaluation of patients.
Ten patients of aneurysmal SAH with clinically symptomatic vasospasm, corroborated on TCD and/or angiography, were included in the study. Eligibility criteria included patients with symptomatic aneurysmal SAH-induced vasospasm refractory to HHH therapy. These patients had no evidence of raised intracranial pressure or infarction. High reliance was placed on TCD studies, particularly in cases where the radiological assessment of the patient was not possible, for example, a patient on a ventilator. Exclusion criteria included patients with: (i) angiographic but asymptomatic vasospasm (ii) obvious infarction or intraparenchymal hematoma (iii) evidence of raised intracranial pressure (iv) major systemic illness, for example cardiac or chest disease or hemodynamic instability (v) unsecured ruptured aneurysms (vi) age below 18 years.
Informed consent was taken from the nearest blood relation of the patient explaining the purpose and nature of the study and its relevance to the therapeutic benefit to the patient. After an initial general physical and neurological examination of the patients the GCS and Hunt and Hess grading for SAH was evaluated. The date of ictus, Fisher's grading for SAH, preoperative angiographic finding, and details of surgical procedure were recorded.
The age of the patients ranged between 33 and 65 years, (mean 50.8 years SD ± 11.2). There were an equal number of male and female patients. All the patients presented with history of sudden onset severe headache while 2 patients had altered sensorium and 1 patient had left hemiparesis. At presentation 2 patients were in Hunt and Hess Grade I, 3 in Grade II, 3 in Grade III and 2 patients were in Grade IV.
Grading of SAH on initial CT scan revealed 5 patients in Fisher's Grade III, 3 in Grade IV and 2 in Grade 1. Eight out of the ten patients who subsequently developed vasospasm were in either Fisher's Grade III or Grade IV.
Anterior communicating artery aneurysm was the commonest aneurysm observed (7/10), while 2 patients had middle cerebral artery aneurysm and 1 had distal anterior cerebral artery aneurysm. All the patients were operated within 24 hours of admission. The majority (7/10) were operated within 5 days of ictus. The time interval between the date of ictus and symptomatic vasospasm ranged from 2 to 18 days with a mean of 9.8 days. The majority (8/10) had no demonstrable vasospasm at the time of presentation. One patient had a hypoplastic right-sided A1 artery.
Nimodipine and HHH therapy were routinely instituted in all the patients. All the patients received HHH therapy varying from 12 hours to 7 days (mean 3.5 days). Once the patients developed symptomatic vasospasm (confirmed on TCD) with no improvement after 12 hours of HHH therapy, they were taken up for intraventricular SNP instillation. CT scan of the head was performed prior to intraventricular SNP instillation to rule out any cerebral infarction / hematoma or hydrocephalus.
The patients were categorized into two groups according to the feasibility of digital subtraction angiography (DSA).
Group A (Angiography + TCD): In these patients a postoperative DSA was possible for radiological demonstration of cerebral vasospasm and intraventricular SNP was instilled during angiography in an attempt to reverse the sequel of acute vasospasm.
Group B (TCD only): In these patients DSA was not possible and hence, based on the TCD finding the diagnosis of cerebral vasospasm was made and intraventricular SNP was periodically instilled to reverse the sequel of cerebral vasospasm.
For Group A patients the extent (site and branches involved) and grading of the vasospasm on DSA was noted by a single observer using constant anatomical reference. Under aseptic precautions a frontal twist drill ventriculostomy was performed. Approximately 10-15 mm of CSF was allowed to drain by gravity at the start of the procedure. Then SNP in the dose of 4mg/1ml was instilled in the ventricle, with close monitoring of the vital signs of the patient. Similar instillation schedules of 4 mg SNP were carried out every 5 minutes and DSA was repeated till reversal of vasospasm and/or opening of perforators was observed. The endpoint of intervention was (i) durable angiography reversal of vasospasm, (ii) failure of the treatment to ameliorate vasospasm up to a maximum of 30 mg, (iii) any adverse effect observed such as vomiting or fall of blood pressure. TCD studies were carried out after 30 minutes of instillation and then every 12 hours for 24 hours and then daily for 3 days along with monitoring the clinical response of the patient.
For Group B patients TCD study was performed to confirm vasospasm at the earliest neurological deterioration. SNP instillation was done at bedside under TCD monitoring through a standard frontal twist drill ventriculostomy under aseptic precaution in a dose of 4mg/ml at the interval of every 5 minutes till there was an improvement in TCD or appearance of an adverse effect. In the last 2 patients, an Ommaya reservoir was placed in the lateral horn of the ventricle at the time of surgery and SNP was instilled at low dose (4 mg) at 8-hourly intervals till the TCD velocity improved. The mean dose requirement of SNP for reversal of vasospasm was 16.2 mg with a range of 8 mg to 30 mg (SD ± 7.75).
Partial to complete reversal of vasospasm was seen in all patients after SNP instillation [Table - 1]. In 1 patient the vessels reverted to normal caliber, in 2 patients to Grade I from Grade II/III vasospasm [Figure:1a], [Figure:1b], [Figure:1c] and in another 2 patients there was opening up of micro circulation/perforator which was revealed as a blush from the perforators of the middle cerebral artery (MCA) [Figure:2a], [Figure:2b], [Figure:2c]. The latter 2 patients presented with weakness of limbs, which improved following opening up of perforators.
All patients showed improvement in TCD velocity on the day after intraventricular SNP therapy. Six patients showed marked fall in TCD velocity after SNP therapy (from >200cm/sec to <110cm/sec). Of the remaining 4 patients 2 showed partial improvement in TCD velocity and another 2 patients showed initial improvement for the first 24 hours followed by worsening.
There was a significant fall in right MCA-TCD velocity on Day 1, Day 2 and Day 3 following intraventricular SNP therapy as compared to pre-SNP velocity. On applying pair t-test, T value was 3.883 and p value was <0.01 which is significant [Figure - 3]. A similar significant fall in left MCATCD velocity was noticed following intraventricular SNP therapy, as compared to pre-SNP therapy, on Day 1, Day 2 and Day 3. On applying pair t-test, T value was 2.743 and p value was <0.05 which is significant [Figure - 4].
Changes in Hunt & Hess grading with Intraventricular SNP Therapy
Hunt and Hess grading of patients with aneurysmal SAH was compared at presentation, at the onset of vasospasm and on Day 1, Day 2 and Day 3 following intraventricular SNP therapy. Instillation of SNP led to the improvement of 2 patients from Hunt and Hess grading III to II on Day 2. Out of 8 patients in Hunt and Hess Grade IV, 2 patients improved to Grade II and another 2 patients to Grade III by Day 3. One patient improved to Grade III for 2 days but reverted back to Grade IV on Day 3. Three patients, however, did not show clinical improvement even though there was a positive response in DSA and TCD. Two patients died, one due to myocardial infarction and one had aspirated, leading to sudden death [Table - 2].
The comparison of Hunt and Hess grading was made at various stages, at the time of presentation, at the onset of vasospasm and at Day 1 and Day 2 of SNP therapy. On applying Wilcoxon test there was a significant correlation (p<0.05). At follow-up after 3 months, 6 out of 10 patients had a good outcome.
Side-effects of intraventricular SNP therapy
Retching or vomiting was the most common adverse effect noted with intraventricular SNP therapy, which responded to antiemitic therapy. Seven patients had either retching or vomiting which occurred once the intraventricular dose of SNP exceeded 8 mg. In the last 2 patients fractionated low-dose schedule was introduced with no adverse effect.
Two patients had relative hypotension of 20 mmHg systolic following intrathecal SNP and the procedure was terminated. In both the patients the hypotension was instantaneously detected and corrected with colloids and ionotropes. Two patients had transient mild elevation of blood pressure after SNP therapy with no adverse effect.
The pathogenesis of vasospasm in SAH appears to be multi-factorial with various theories being put forward to explain the occurrence of vasospasm. Oxyhemoglobin, a breakdown product of hemoglobin from lysed RBC in the cisternal CSF, is believed to be the spasmogen involved in the genesis of vasospasm. Other substances derived from subarachnoid blood have not been shown to produce smooth muscle contraction., Lately, vasoactive endothelium derived peptide, called endothclin-1 (ET-1), was isolated and its effect on smooth muscle contraction demonstrated., Oxyhemoglobin liberated after SAH appears to be simultaneously capable of activating the gene for this potent vasoconstrictor, increasing levels of ET-1 mRNA in the CSF and of also removing the influence of the potent vasodilator NO, the physiological antagonist of ET-1, from the blood vessel wall by direct binding. In a study by Suzuki et al, the concentration of ET-1 increased before the manifestation of cerebral vasospasm in 7 out of 8 patients. In 13 out of the 15 patients without vasospasm, the concentration of ET-1 in the CSF decreased with time.
Basal tone in cerebral blood vessels is maintained by a factor known as endothelium derived relaxing factor (EDRF), which was identified as NO in 1987 by Moncada and associates, which contributes by maintaining 10 to 20% of the vessel caliber.
As the fundamental pathophysiology of delayed cerebral vasospasm is yet to be revealed, the treatment for the condition, till date, has been relatively non-specific, for example calcium channel blockers, HHH therapy and selective mechanical (balloon) cerebral angioplasty.,,,,
Orgitano et al (1990), in a study of prophylactic HHH therapy after early surgery in 43 patients of aneurysmal SAH, demonstrated vasospasm in 16 (37%) patients, 15 of whom had ischemic deficit. This ischemic deficit resolved with HHH therapy. Soloman et al (1988) treated 56 patients of aneurysmal SAH with early surgery followed by prophylactic HHH therapy. Though 86% patients made good recovery, 7% had mild and 5% had major deficits.
ET-1 and NO are important factors in maintaining dynamic equilibrium in vasomotor tone. Disequilibria between the vasomotor effects of these molecules results in unmitigated vasoconstriction. Transient reversal of vasospasm has been demonstrated in several studies after intrathecal, intravenous or intra-arterial application of short acting NO donors.
lntrathecal SNP therapy is a potentially useful treatment for chronic delayed type of human cerebral vasospasm following aneurysmal SAH with affinity for both larger conductance and smaller resistance vessel., The NO molecule derived from SNP penetrates the adventitial side of the blood vessel, activates the soluble form of guanylate cyclase which in turn converts guanosine 5' triphosphate to cyclic guanylic acid. Through this latter second messenger, protein kinase activation takes place and subsequently relaxation of the vascular smooth muscle occurs resulting in vasodilatation. Relatively thin walls of smaller vessels could conceivably render them more readily susceptible to the effect of NO donors, administered intrathecally, causing them to respond faster and improve circulation time. Intrathecal SNP may penetrate the brain parenchyma by way of ependyma of ventricle, its effect in this way becoming independent of ventricular CSF circulation.,
Thomas et al, in January 1999, published their first experience with intrathecal administration of SNP in 3 humans and showed improvement in all the patients with no adverse outcome. The study did not establish any optimum dose as it was carried out by dose escalation within the imposed limitation of 30 mg per procedure. Demonstration of infarction or significant intraparenchymal hematoma was a relative contraindication for intrathecal SNP not only because of the risk of hemorrhagic conversion of infarction by reperfusion but also because of the potential exotoxic effect of NO.,
Although a substantial vasodilatation of large caliber conductance vessel in response to SNP was demonstrated, the improvement in collateral circulation, dilation of smaller resistance vessel and shortening of circulation time, sometimes without a dramatic change in the size of conductance vessels, seemed to be an equally important effects of this treatment as was demonstrated in the present study. Improved circulation time alone, at a constant cerebral perfusion pressure may imply enhanced circulation at anatomic levels below angiographic resolution., The latest study on cerebral hemodynamics and oxygenation in patients of poor grade aneurysms demonstrates improved PbrO2 and cerebral blood flow after intrathecal SNP therapy.
In the study by Thomas et al, 3 episodes of brief hypotension (<1 min duration) were noted, all of them associated with high doses of intrathecal SNP. Similar episodes were noted in the present series though there was no episode of profound hypotension, intracranial hypertension or cynate toxicity. In a subsequent report, 6 out of 10 patients experienced nausea, the same being noted in 7 out of 10 patients in the present series.
In the present study, 60% cases showed reversal of vasospasm after intraventricular doses of SNP ranging between 12 mg and 30 mg. One patient had complete reversal while in 2 patients reverted to Grade I vasospasm. In 2 other cases there was appearance of blush from MCA, representing opening of perforator and lenticulostriate branches, both showing improvement in motor deficit which manifested at the onset of vasospasm. These observations demonstrate the efficacy of intraventricular SNP therapy in the reversal of vasospasm of large conductance as well as smaller resistance vessels.
Angiographic evidence of the opening up of perforators, even when the TCD velocity was not significantly raised, in patients who manifested with focal deficit has not been demonstrated earlier with intrathecal SNP therapy. This exposes the drawback of TCD in picking up vasospasm of smaller vessels (perforators), which can be reversed with intraventricular SNP therapy. Though angiographic reversal of vasospasm was not complete in all cases, reduction of flow velocity on TCD study was evident in all. This suggests that reduction of velocity on TCD study does not go hand in hand with angiographic reversal of vasospasm.
Since frontal twist drill ventriculostomy for instillation of intraventricular SNP delayed the onset of therapy in a neurologically deteriorated patient, the placement of an Ommaya reservoir in the ventricle at the time of surgery, in suspected patients, made it convenient for prompt instillation of SNP which could be repeated at bedside on a fractionated dose schedule. The Ommaya reservoir was subsequently removed.
The study relates to the following observations: (i) Intraventricular SNP increases cerebral blood flow reducing vasospasm effectively (ii) It effectively opens up perforators/lenticulostriate branches, leading to an improvement in motor deficit in all patients (iii) Vomiting was the commonest adverse effect (iv) A low intermittent dose (4mg/ml each) schedule can avoid the complication of vomiting (v) Fall in systemic blood pressure, if occurs, is marginal and correctable. However, the study needs to be further expanded to a larger patient population for better statistical correlation.