The 10,000 fold effect of retrograde neurotransmission, a new concept for stroke revival: use of intracarotid sodium nitroprusside.
The early start of pulsations with physiological recovery (by electrical impulse generation) is the goal of any intervention performed on infracted brain. This pilot study serves the ultimate goal of physiological recovery.
For physiological recovery, we must attempt to understand the normal and abnormal impulses, synapses and the generation of action potential cascade that are well documented by clinical and nonclinical studies. Two mechanisms for acute, and one for chronic cases is being proposed here.
FOR-ACUTE (3-7 days) CASES-RETROGRADE-NEUROTRANSMISSION-THEORY: In normal excitatory-impulses (at synapse), glutamate (from presynaptic-membrane) activates NMDA receptors (associated with nitric-oxide synthetase (NOS) on postsynaptic-membrane for further propagation by calcium-calmodulin-complex. (6-8) NOS produces NO and then NO cloud at synapse thus bridging the microgaps. (8-11) NO travels backward across this chemical synapse (8) to bind to its receptor (NO receptor/sGC-soluble guanalyl cyclase), regulating anterograde-neurotransmission; this process is called "retrograde neurotransmission" (7, 12) and allows neural circuits to create feedback-loops.
NO-receptors (well equipped with a ligand-binding-site and a transduction-domain) differ in some interesting properties. The ligand-binding site (heme, such as hemoglobin in blood) when incorporated into the receptor-protein, exhibits >10, 000-fold higher affinity for NO than for oxygen (THE 10, 000 FOLD EFFECT) (13, 14) and is completed in 20 msec (9) decays in 200 msec. (15) This retrogradeneurotransmission-like action of NO11, 16 is also shown by carbon monoxide (17) and platelet-activating factor. (10, 18)
IMPULSES TOO-HIGH/TOO-LOW: NO can up (19) or down regulate (20, 21) the oncoming-impulses. In conditions of high-intensity impulses such as schizophrenia (22) and obsessive-compulsive disorder, (23) NO downregulates the impulses; in conditions of low-intensity impulses such as depression with low-serotonin levels, NO upregulates the impulses (24) (FIGURE I A).
IN THE ABSENCE OF IMPULSES: In cases with no impulse (NORMAL-ANTEROGRADENEUROTRANSMISSION, including synaptic activity, with no RETEROGRADE-NEUROTRANSMISSION), NO-donors have shown promising results in generating impulses by increasing the frequency of spontaneous miniature EPSPs by NO via RETEROGRADE-NEUROTRANSMISSION in vitro in rats (25) thus bypassing normal ANTEROGRADE-NEUROTRANSMISSION (FIGURE I B). This cascade relaxes the smooth-muscles of perforators.
FOR-ACUTE (3-7 days) CASES-VASOSPASM-THEORY: NO is a very potent vasodilator 26- 28. SNP excels in emergency treatment of hypertension (29) by vasodilation, which is instantaneous (onset within 30 seconds; peak in 2-5 minutes). (30) Intrathecal-sodium-nitroprusside has been used in vasospasms induced by subarachnoid-hemorrhage. SNP acts on NOS present at the adventitial side of perforators, triggering NO release thus relaxes smooth muscles of perforators via cAMP pathway.
The impact of the intrathecal (31,32) and intraventricular (33) SNP in vasospastic cases on the larger-caliber vessels appears to be minimal, and the decreased cerebral circulation time indicates improved cerebral blood flow via microcirculation. (34-36) Oral Sildenafil have been studied but only to relieve vasospasms caused by SAH. (37-39) Studies on intra-arterial(for ergotism patients (40-43) and intracarotid (for measurements of cerebral blood flow)were conducted on dogs, (44) cats (45) and then on normal human beings who were subjected to DSA for other reasons. (46, 47)
Various treatment options available are for salvaging the penumbra region and to relieve obstruction via thrombolysis, but no study for vasodilation of perforators at penumbra and to induce electrical impulses by EPSPs (25) via the very potent RETEROGRADE-NEUROTRANSMISSION by bypassing the ANTEROGRADE-NEUROTRANSMISSION is available.
FOR-CHRONIC (>7 days) CASES: LTP (LONG-TERM-POTENTIATION): Endocannabinoidsanandamide and 2-AG are primary-retrograde-messengers in brain and may also play an important role in retrograde-signaling in long-term-potentiation, which is crucial for memory &/or learning, (9,19,20,21,48,49,26-28,50-53) as nitric-oxide. (19,20) The NO-cGMP pathway plays a role in LTP at many synapses throughout the CNS and even at neuromuscular-junction.
This same principle of "generation of impulses from presynaptic-region to post-synapticregion by highly-potent RETEROGRADE-NEUROTRANSMISSION (10,000-FOLD-EFFECT), the vasodilation of arteriolar perforators and long-term-potentiation are the bases of the authors' hypotheses for treating acute/chronic stroke cases.
MATERIALS AND METHODS: Clearance was obtained from the local-ethical-committee (number02/NC/SUL/2012). Potential benefits and significant risks, specifically uneasiness/vomiting /retching/diaphoresis/apprehension/restlessness/perspiration/muscle twitching/ palpitation / dizziness and abdominal pain and possible hypotension, were discussed with all patients and/or their families. Written and video consent were obtained from relatives of patients for INTRACAROTID-SODIUM-NITROPRUSSIDE and video-recordings of pre- and post-injection phases with Trans-Cranial-Doppler (TCD).
The stroke team was notified of 178-patients suspected of having strokes of >3days previously; 96 were disqualified, and 82 qualified for the study. The most common reasons for disqualification from INTRACAROTID-SODIUM-NITROPRUSSIDE therapy were intracerebral-hemorrhage (n=48), acute stroke diagnosis in which thrombolysis was acutely needed (rTPA given) (n=32), a non-stroke diagnosis (n=10) and minor or rapidly resolving symptoms (n=6). 82-stroke-patients, the control-group (10/82) and INTRACAROTID-SODIUMNITROPRUSSIDE- group (72/82) were formed. Control-group was subdivided into two subgroups.
First-subgroup (5/10) did not undergo any super fusion, and the other (5/10) super fused with Dex 5% between Dec-2012 and Feb-2014, treated at NEURO-CENTER prospectively. INTRACAROTIDSODIUM-NITROPRUSSIDE-GROUP (72-patients) was subdivided according to BASELINE-NIHSS score. Three groups (5-15, moderate; 16-20, moderate to severe; and 21-42, severe) were formed based on the NIHS-Score. All the NIHSS-grades were again subdivided according to time of infusion, from 3-7 days and >7 days.
Mean age of our patients was 63.75 years (range 45-72). Out of the 72-patients who were given INTRACAROTID-SODIUM-NITROPRUSSIDE, 52 were males. Co-morbid-illnesses in form of hypertension/diabetes/hypercholesterolemia were present in 72(100%)/52(72.22%)/72(100%) patients, respectively. Additionally, atrial fibrillation/congestive-heart-failure/coronary-artery-disease were present in 10(13.88%)/5(6.94%)/28(38.88%) patients, respectively.
There was a history of prior stroke in 4 patients (5.55%). Mean-blood-pressure at admission was 170/98 and mean-maximum-pretreatment was 182/100 mmHg. Fifty-four (75%) of 72-patients were smokers. Detailed blood-pressure monitoring was performed due to the possible hypotensive action of SNP.
Variables recorded: time of symptom onset, arrival time, CT scan and/or MRI and TCD and INTRACAROTID-SODIUM-NITROPRUSSIDE administration time. Extensive-neurological-examination including BASELINE-NIHSS was performed in all patients. Other parameters noted were demographic profile, stroke risk-factors, ECG-examination, baseline CT-scan findings/MRI-study, platelet-aggregation-activity monitoring (bleeding-time), PT/PC/APTT and INR level.
Using TOAST-criteria, patients were classified into: large-artery-atherosclerotic=32; cardioembolic=16; small-vessel-occlusion=8; other-determined-etiology=4; undeterminedetiology=12.
Inclusion and exclusion criteria are shown in (TABLE I).
Patients received pretreatment for nausea in form of ondansetron HCl (32.0mg/IVpush) 15-minutes before treatment. Meticulous photoprotection/sterile techniques were observed for all aspects of delivery of medication as well as its formulation. Powdered-SNP was sterilely reconstituted with 200ml 5% dextrose with 50mg of the SNP. Patients were hydrated and INTRACAROTID-SODIUM-NITROPRUSSIDE given with simultaneous IV injection of 1 ml mephentermine to combat the ensuing SNP-related hypotension.
Each of our patients received 0.01mg/kg of INTRACAROTID-SODIUM-NITROPRUSSIDE, up to a maximum of 2ml (0.5mg), based on titration of hypotension (stopping at the very point at which the anesthetists declared hypotension had started). The whole calculated dose was given as a bolus dose using sterile technique, injected slowly over 3 minutes through a 25 G LP needle directly into the ipsilateral-carotid-artery.
We waited for 90 sec for the recovery, while conducting continuous TCD studies. NIHS-scores were recorded at baseline/90-sec/2-h/24-hrs/7-days/&/2-months. The Barthel-index was recorded at 2-months.
This study corroborates earlier impressions regarding the safe limits of doses of SNP in intrathecal, (32,33) intraventricular, (34) intra-arterial for ergotism (38-41) and intracarotid (44,45) administration. We injected only 0.5mg (2ml of reconstructed fluid, i.e., 0.01mg/kg/bo/wt). This study also supports safety of INTRACAROTID-SODIUM-NITROPRUSSIDE in intensive care/emergency room.
Heparin/aspirin/clopidogrel/&/Antihypertensives were given during hospital stay. High-protein (arginine-rich) diets were started. Peak blood pressure was recorded during INTRACAROTID-SODIUM-NITROPRUSSIDE administration as well as during the first 24 h after INTRACAROTID-SODIUM-NITROPRUSSIDE.
Using Oxford stroke classification (BAMFORD's classification), LACS (LACUNAR-STROKE) was found in 16/72 patients (22.22%), PACS (PARTIAL-ANTEROGRADE-NEUROTRANSMISSIONERIORCIRCULATION-SYNDROME) was found in 36/72(50%), TACS (TOTAL-ANTEROGRADE-NEUROTRANSMISSIONERIOR-CIRCULATION-STROKE) was found in 12/72(16.66%) and POCS(POSTERIOR-CIRCULATION-SYNDROME) was found in 8/72(11.11%).
Mean time of INTRACAROTID-SODIUM-NITROPRUSSIDE injection was 9.5 days (range 3-24) after stroke onset. (TABLE II: CLINICAL CHARACTERISTICS (PRE-TREATMENT). Mean-length-of-hospitalization was 4-days. The MEAN-BASELINE-NIHSS-SCORE was 21.11(range 10-33). PreINTRACAROTID-SODIUM-NITROPRUSSIDE and post-INTRACAROTID-SODIUM-NITROPRUSSIDE clinical examination was video-recorded.
MRIs were performed (FIGURE II A TO D, FIGURE III A TO D, FIGURE IV A TO D AND FIGURE V A). TCD was noted in pre-(FIGURE V B; PRE INTRACAROTID-SODIUM-NITROPRUSSIDE) and post-INTRACAROTID-SODIUM-NITROPRUSSIDE (FIGURE V C AND D; POST INTRACAROTID-SODIUMNITROPRUSSIDE).
TABLE III: BASELINE AND POST-INTRACAROTID-SODIUM-NITROPRUSSIDE CHARACTERISTICS WITH NIHSS CHANGES.
TABLE IV: BAMFORD'S CLASSIFICATION AND CHANGES AFTER INTRACAROTID-SODIUMNITROPRUSSIDE.
RESULTS: We obtained telephone or clinic follow-up with patients and caregivers in cases for next two months and assessed Barthel Index of Activities of Daily Living.
For analysis based on NIHSS GRADING, results were as follows:
1. NIHSS 5-15(12/72-CASES/16.66%): INTRACAROTID-SODIUM-NITROPRUSSIDE-GROUP had a MEAN-BASELINE-NIHSS-SCORE 10-points, whereas CONTROL (no superfusion;dex5%) scored 19.14/20.2 points, respectively. Patients were given INTRACAROTID-SODIUMNITROPRUSSIDE at 11-days poststroke. After 90-sec, MEAN-MOTOR-CHANGE in NIHSS of INTRACAROTID-SODIUM-NITROPRUSSIDE-group was 2.4 points/21.81% decrease. 2-hrs, 5.26% decrease. 24-hrs, 0.43% increase, which decreased until 2-months after stroke. At 2 months, Barthel's-score was 85%, and mRS was 0-1.
2. NIHSS (16-20(24/72CASES/32.33%): INTRACAROTID-SODIUM-NITROPRUSSIDE-GROUP had a MEAN-BASELINE-NIHSS-SCORE 18.33 points. Patients were given INTRACAROTID-SODIUMNITROPRUSSIDE at 10.16-days poststroke. After 90-sec, MEAN-MOTOR-CHANGE in INTRACAROTID-SODIUM-NITROPRUSSIDE-GROUP MEAN-BASELINE-NIHSS-SCORE was 2.17 POINTS/18.33% decrease. After 2-hrs, 11.83% decrease and after 24-hrs 12% increase, decreased until 2-months. At 2-months, Barthel's-score was 88.33%, and mRS was 1.
3. NIHSS BETWEEN 21 and 42 (36/72 CASES, 50%): INTRACAROTID-SODIUM NITROPRUSSIDE GROUP had a MEAN-BASELINE-NIHSS-SCORE 28.33 points. Patients were given INTRACAROTID-SODIUM-NITROPRUSSIDE at 8.88 days poststroke. After 90-sec, MEAN-MOTOR-CHANGE in INTRACAROTID-SODIUM-NITROPRUSSIDE-GROUP MEAN-BASELINE-NIHSS-SCORE was 3.33 POINTS/11.75% decrease. After 2-hrs, 7.15% decrease and after 24 hrs, 3.34% increase decreased until 2-months. At 2-months, the Barthel's-score was 72.50% and mRS was 2.
For analysis, we defined outcomes as follows:
1) EXCELLENT-OUTCOME-NIHSS of > 3 in 90-sec and Barthel-Index of > 80% after 2-months.
2) GOOD-OUTCOME-NIHSS of 1-2 in 90-sec and Barthel-Index of 70-80% after 2-months.
3) FAIR-OUTCOME only subjective/TCD showed improvement of one-grade in 24-hrs, with the improvement sustained/increased even after 7-days, with Barthel-Index of 60-70% after 2 months.
4) POOR-OUTCOME patient shows no improvement clinically/TCD for up to 7-days, with Barthel-Index of 50-60% after 2-months.
For video verifications, the case-videos can be viewed on YouTube, at URLs provided in online supplement.
1) EXCELLENT-OUTCOME-CASES (16/72-CASES; 22.22%): INTRACAROTID-SODIUM NITROPRUSSIDE-GROUP with MEAN-BASELINE-NIHSS-SCORE 19-points compared to CONTROL (no superfusion/dex5%), which scored 19.14/20.2 points respectively. Patients were given INTRACAROTID-SODIUM-NITROPRUSSIDE at 8.75 days post-stroke. After 90 sec, the MEAN-MOTOR-CHANGE in INTRACAROTID-SODIUM-NITROPRUSSIDE-GROUP NIHSS was 3.5 POINTS/18.42% decrease. After 2-hrs, 14.51% decrease and after 24-hrs/43% increase was noted. Mean-recovery was decreased (5.75 POINTS/30.26%) from BASELINE-INTRACAROTIDSODIUM-NITROPRUSSIDE-NIHSS-SCORE but increased compared to 2-hrs POSTINTRACAROTID-SODIUM-NITROPRUSSIDE. Comparing CONTROL (no superfusion/dex 5%) to INTRACAROTID-SODIUM-NITROPRUSSIDE-GROUP, mean change in NIHSS was 1/0.4-POINTS, 5.15/1.98% decrease, respectively, which decreased until 2-months after stroke.
2) GOOD-OUTCOME-CASES (28/72-CASES; 38.88%): INTRACAROTID-SODIUM-NITROPRUSSIDE -GROUP had MEAN-BASELINE-NIHSS-score 18.71 points. Patients were given INTRACAROTIDSODIUM-NITROPRUSSIDE at 7-days post-stroke. After 90-sec, MEAN-MOTOR-CHANGE in INTRACAROTID-SODIUM-NITROPRUSSIDE-GROUP NIHSS 1.71 POINTS/9.13% decrease. After 2-hrs 1.71 POINTS/10.11% decrease, after 24-hrs 0.71 POINTS/4.71% increase. Mean recovery was decreased POST-BASELINE INTRACAROTID-SODIUM-NITROPRUSSIDE-NIHSS-SCORE (1 POINT/5.88%) but increased POST-2-hrs-INTRACAROTID-SODIUM-NITROPRUSSIDE then decreased until 2-months after stroke.
3) FAIR-OUTCOME-CASES (8/72 CASES/11.11%): INTRACAROTID-SODIUM NITROPRUSSIDE - GROUP had MEAN-BASELINE-NIHSS-score 19.5-points. Patients were given INTRACAROTID-SODIUM-NITROPRUSSIDE at 22 days post-stroke. No recovery was noted after 90-sec or after 2-hrs. After 24-hrs, 1 POINT/1.12% decrease, at 7-days 3-POINTS/2.37% decrease and at 2-months 1.5-POINTS/1.01% decrease.
4) POOR-OUTCOME-CASES (20/72 CASES/27.77%): INTRACAROTID-SODIUM-NITROPRUSSIDE -GROUP had MEAN-BASELINE-NIHSS-score 30.4-points. Patients were given INTRACAROTIDSODIUM-NITROPRUSSIDE at mean 22 days poststroke. No recovery noted after 90-sec, 2-hrs or 24-hrs. At 7-days, there was a decrease of 1.8-POINTS/2.92%, at 2-months decrease of 1.75 POINTS/2.18%.
COMPARISON OF DIFFERENT COMBINATIONS OF POSTSTROKE DAYS OF INTRACAROTIDSODIUM-NITROPRUSSIDE:
a) 3 DAYS-<7days: Mean time was 4.72-days. MEAN-BASELINE-NIHSS-SCORE was 23 points (range 10-32). After 90-sec, MEAN-CHANGE was 3.09-points/13.47% (range 2-5). After 2-hrs, 1.27-points/4.28%. After 24-hrs, 0.27-points/1.01%. After 7-days, 4.72-points/7.16%. After 2 months, 7.72-points/10.61%.
b) >7 days: Mean time was 17-days. MEAN-BASELINE-NIHSS-SCORE was 20.71 points. After 90 sec, MEAN-CHANGE was 2.28 points/11.05% (range 0-5). After 2-hrs 1.57-points/8.52%. After 24-hrs, 0.44-points/0.28%. After 7-days, 1.28-points/5.93%. After 2-months, 2-points/7.1%.
Considerable reduction in stroke-severity was noted in 44/72 patients (MEAN-CHANGENIHSS after 90-sec, 2.6-points/13.85% (range 1-3). This reduction was accompanied by changes in TIBI flow grades on TCD as well as in clinical assessment of limb strength.
A remarkable clinical course was noted in cases numbered 11, 44 and 71, who presented with a right-sided weakness due to an occlusion in left middle cerebral artery at post-stroke mean-day-4.6.
Complete instantaneous improvement (power increased from grade 0 to grade 2-3) was noted, as seen in video recordings, after only 90 sec of INTRACAROTID-SODIUM-NITROPRUSSIDE with TCD-PULSATIONS.
Using Oxford stroke classification (BAMFORD's-classification).
LACS (LACUNAR-STROKES) 12/72-patients (16.66%), with BASELINE-NIHSS-SCORE 13.33 points; MEAN-CHANGE 90-sec/3.3 points/24.98%; at 2-hrs, 2.34-points/23.40%; at 24-hrs, 1.67 points/21.80%; at 7-days 5.67-points/60.77%; BARTHEL's-SCORE was 85%.
PACS(PARTIAL-ANTERIOR-CIRCULATION-SYNDROME)36/72-patients(50%), with BASELINE-NIHSS- SCORE 23.44-points; MEAN-CHANGE at 90-sec 2.89-points/12.32%; at 2-hrs, 1.33 points/6.47%; at 24-hrs, 0.78-points/4.05%; at 7-days, 15.12-points/75.60%; BARTHEL's-SCORE was 80.55%.
TACS (TOTAL-ANTERIOR-CIRCULATION-STROKE) 16/72-patients (22.22%), with BASELINENIHSS- SCORE 30-points; MEAN-CHANGE 90-sec 3.25-points/7.47%; at 2-hrs, 2-points/7.47%; at 24 hrs, 0.75-points/3.03%; at 7-days, 20.5-points/80.39%; BARTHEL's-SCORE was 71.66%.
POCS (POSTERIOR-CIRCULATION-SYNDROME)8/72-cases(11.11%), with a BASELINENIHSS- SCORE 13.5-points; MEAN-CHANGE 90-sec 0.5-points/3.70%; at 2-hrs, 0-points, at 24-hrs, 0.5-points/3.84%; at 7-days, 5.5-points/44%; BARTHEL's-SCORE was 85%.
TACS (16-patients). In 9-cases, ICA was stenosed and produced a focal significant flow-velocity-increase (70cm/s at terminal ICA-bifurcation (temporal-window). ICA-MFV (mean-flow-velocity)was greater than in the MCA and contralateral ICA. In 7-cases, ICA-SIPHON was OCCLUDED, producing no signals at 62-70 mm via transorbital-approach. More findings included were collateral flow in posterior and Anterior communicating arteries and a blunted MCA signal and contralateral ICA compensatory velocity increase.
PACS (36 patients). In 14-cases, MCA-STENOSIS was observed associated with MFV (100 cm/s). There was also some turbulence/murmur/decreased flow resistance distal to stenosis, and increased unilateral A1-ACA-flow-velocities. M1-MCA-stenosis in 12-cases produced a significant focal increase in MFV-80 cm/s, and PSV-140 cm/s, and an interhemispheric MFV-difference of >30% was noted. ACA-stenosis in 5-cases produced focal significant flow-velocity increase (80cm/s, ACA>MCA). MCA-OCCLUSION-In 8-cases of M1-MCA-occlusion, there were no signal at any depth (4565 mm) via transtemporal-approach. M2-MCA-occlusion in 5-cases produced a unilateral MFV decrease of >30% M1-MCA and a high-resistance waveform (PI 1.2). There was also a compensatory flow-velocity-increase in ACA. ACA-occlusion in 5-such cases, no-signals were found at depths of 6274mm.
POCS (8 patients). In 4-cases, PCA-stenosis produced a focal significant increase in flow velocity >50 cm/s, and PCA MFV >ACA, ICA, or MCA MFV. Stenosis of the basilar artery in 4-cases at depths ranging from 80mm (proximal) to 100mm (distal) noted. Focal significant flow-velocity increase >60 cm/s and BA MFV>MCA MFV. Terminal VA-stenosis 1-case produced a focal significant flow-velocity increase (50 cm/s and VA MFV>BA MFV).
For LACS, we were not able to insonate deeply enough and therefore relied on MRI and CT findings from the pre-INTRACAROTID-SODIUM-NITROPRUSSIDE phase.
Of these 72 patients, 75.88% of the Barthel Index scores indicated near-normal functional status.
DISCUSSION: NINDS study gave a brain salvaging time of 3 hrs for anterior circulation and 6 hrs for posterior circulation. A significant difference in our experience was the effectiveness of treatment within an average of 9.5 days, and, due to very potent 10, 000-fold effect, INTRACAROTID-SODIUM-NITROPRUSSIDE generates ANTEROGRADE-NEUROTRANSMISSION via RETEROGRADE-NEUROTRANSMISSION action thus bypassing the normal ANTEROGRADE-NEUROTRANSMISSION (which is usually absent in stroke). We did not deviate from the standard protocol of thrombolysis within the specified time by choosing only those patients who were out of range for thrombolysis (from 3rd day onwards). None of our patients developed any form of intracerebral hemorrhage (as found in the NINDS study), which suggests a good safety profile for INTRACAROTID-SODIUM-NITROPRUSSIDE.
Just after 90-sec, cases with moderate NIHSS-scores (5-15) improved excellently (21.27%)compared to moderate to severe cases (9.11%)and severe cases (2.36%) if INTRACAROTIDSODIUM-NITROPRUSSIDE was performed within 3-7 days (18.92%)versus >7 days (11.05%). This means that results with INTRACAROTID-SODIUM-NITROPRUSSIDE, if administered between 3-7 days, are 1.71 times better than those for >7 days. Further, LACS showed the best results (24.98%), followed by PACS (12.32%) and then the other types of stroke. Video recordings also showed remarkable results of increases of 3.3 points in LACS, 3.25 points in TACS and 1.33 points in PACS within 90-sec. These patients all invariably showed a decremental decrease after 2-hrs (patient improvement) and an increase in NIHSS (patient deterioration) after 24-hrs.
Those patients who showed deterioration in their NIHSS scores at 24-hrs post-INTRACAROTID-SODIUM-NITROPRUSSIDE return back to 7-day NIHSS-status after 24-hrs. This deterioration might be due to superoxide (SO) formation in pathological brain region. The level of serum superoxide dismutase (SOD) is inversely correlated with size of infarction on CT scan and severity of the neurological deficits. Decreased SOD activity recovered within a mean of 5-days to serum values of control patients. (54) Our second hypothesis proposed that synaptic vesicles were swiftly used up by ANTEROGRADE-NEUROTRANSMISSION and RETEROGRADE NEUROTRANSMISSION, creating local depletion, pulling raw material (L-Arginine/&/oxygen (55) from cell body, approximately within a week. (6-8) We therefore advised an arginine-rich-diet. Our clinical findings (7 days post-INTRACAROTID-SODIUM-NITROPRUSSIDE) show a decrease in NIHSS-score after 7-days, supporting above two hypotheses-superoxide-ions is washed away by serum SOD along with restoration of material from cell-body.
Four-cases (POCS) did not respond until 24-hrs after treatment, as they were given INTRACAROTID-SODIUM-NITROPRUSSIDE at mean of 20.22-days post-stroke; further, they had brainstem(minute left-pontine or right-midbrain) infarcts (POCS), and we injected into the commoncarotid-artery, which is separate from posterior-circulation.
They started moving their upper/lower-limbs after 24-28 hrs, perhaps because of the long-term-potentiation function of NO, (21,48) yet to be evaluated. The NO-cGMP pathway forms the basis of memory and learning in the brain. These patients were walking with support by 3-4 days POSTINTRACAROTID-SODIUM-NITROPRUSSIDE, and their NIHSS-SCORES averaged 10.22 points on the 7th day POST-INTRACAROTID-SODIUM-NITROPRUSSIDE (Youtube video-URL attached).
INTRACAROTID-SODIUM-NITROPRUSSIDE-GROUP TIME-COMPARISON study reveals definite and quick improvement in the 3-7 day group (INTRACAROTID-SODIUM-NITROPRUSSIDE at 90 sec/3-POINTS/13.47%) compared to the >7* day group (INTRACAROTID-SODIUMNITROPRUSSIDE at 90 sec/2.28-POINTS/11.05%).
Comparative study of patients with EXCELLENT and GOOD RESULTS showed a swifter improvement (90 sec/2.6-points/13.85%) than the fair group (24 hrs/1-POINT/5.12%), and there was no response in the poor group within 7 days of treatment.
Comparative study, as per BAMFORD's classification (56), showed a specific correlation between the site of blockage and the POST-INTRACAROTID-SODIUM-NITROPRUSSIDE effect. The best response was observed with the LACS patients (3.3-points/24.98%), followed by PACS (2.89 points/12.32%), and then TACS (3.25-points/10.83%), with the smallest response in POCS patients (0.5-points/3.70%). This discrimination may be because the posterior circulation is too far from the carotid arteries, but the cause has yet to be evaluated. In future, we plan to superfuse fourth ventricle in POCS cases.
In cases of TACS, the TCD in the PRE-INTRACAROTID-SODIUM-NITROPRUSSIDE phase in ipsilateral ICA showed minimal flow signals, but soon after INTRACAROTID-SODIUM-NITROPRUSSIDE, it showed dampened flow signals (pulsatile signal with normal acceleration and mean flow velocity of 30% with positive end diastolic flow compared to the normal side GRADE 2 TIBI grading system); in two cases (case numbers 15 and 60), blunted flow signal was detected with delayed systolic flow acceleration and mean flow velocity of less than 30 cm/sec (57, 58) perhaps because the perfusion performed was on day, (24,42) and the BASELINE-NIHSS was. (33)
The present study has certain limitations, such as not having CT perfusion, DSA & MRA in the pre- and post-injection periods with DWI and PWI, due to the unavailability of higher-end MRI and CT perfusion-enabled software for CT scanning at our setup. We plan to conduct a broader study including all of the above investigations in the future. No patient was given blood transfusion.
CONCLUSIONS: INTRACAROTID-SODIUM-NITROPRUSSIDE treatment is effective at mean of 9.5 days post-stroke (3-24 post-stroke-day) within 90-seconds; it shows a small detrimental response after 24-hrs followed by an incremental response until the seventh-day with a Barthel-score of 75.88% at two-months. SNP is a very potent RETEROGRADE-NEUROTRANSMISSION (via the 10, 000-FOLDEFFECT) safe (does not cause hemorrhage-acts at microcirculation), universally available, affordable and administrate in a wide time period. A larger, double-blinded, controlled, multicentric, randomized trial study is needed to quantify the effect of INTRACAROTID-SODIUM-NITROPRUSSIDE in stroke.
(1.) Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke (NINDS) and rt PA Stroke study group. N Engl J Med 1995; 333:1817.
(2.) Association of outcome with early stroke treatment: Pooled analysis of ALANTIS, ECASS AND NINDS rt-PA stroke trials. Lancet 2004; 33: 768-74.
(3.) MV Padma, MB Singh, R Bhatia, A Srivastava, M Tripathi, G Shukla, et al. Hyperacute thrombolysis with IV rtPA of acute ischemic stroke: Efficacy and safety profile of 54 patients at a tertiary center in a developing country. Neurology India 2007; 55:46-9.
(4.) Vijay Kumar Sharma et al. Ultrasound Assisted Thrombolysis in Acute Ischemic Stroke: Preliminary Experience in Singapore. Ann Acad Med Singapore 2008; 37: 778-82.
(5.) Susan D, Tiukinhoy-Laing, Shaoling Huang, Melvin Klegerman, Christy K. Holland, David D et al. Ultrasound-facilitated thrombolysis using tissue-plasminogen activator-loaded echogenic liposomes. Thromb Haemost 1997; 78;1063-8.
(6.) Kennedy MB. Signal-processing machines at the postsynaptic density. Science. 2000; 290: 750754.
(7.) Sabatini BL, Oertner TG, Svoboda K. The life cycle of Ca [2+] ions in dendritic spines. Neuron. 2002; 33: 439-452.
(8.) Bellamy TC, Garthwaite J. Sub-second kinetics of the nitric-oxide receptor, soluble guanylyl cyclase, in intact cerebellar cells. J Biol Chem. 2001b; 276: 4287-4292.
(9.) Liu X, Srinivasan P, Collard E, Grajdeanu P, Zweier JL, Friedman A. Nitric-oxide diffusion rate is reduced in the aortic wall. Biophys J 2008; 94: 1880-1889.
(10.) Kato K, Clark G, Bazan N, Zorumski C. Platelet-activating factor as a potential retrograde messenger in CA1 hippocampal long-term potentiation. Nature 1994; 367 (6459): 175-9.
(11.) Garthwaite J, Boulton CL. Nitric-oxide signaling in the central nervous system. Annu Rev Physiol. 1995; 57: 683-706.
(12.) Regehr Wade G, Carey Megan R, Best Aaron R. Activity-Dependent Regulation of Synapses by Retrograde Messengers. Neuron July 2009; 63 (2): 154-170.
(13.) Martin E, Berka V, Bogatenkova E, Murad F, Tsai AL. Ligand selectivity of soluble guanylyl cyclase: effect of the hydrogen-bonding tyrosine in the distal heme pocket on binding of oxygen, nitric-oxide, and carbon monoxide. J Biol Chem. 2006; 281: 27836-27845.
(14.) Stone JR, Marletta MA. Soluble guanylate cyclase from bovine lung: activation with nitric-oxide and carbon monoxide and spectral characterization of the ferrous and ferric states. Biochemistry. 1994; 33: 5636-5640.
(15.) Lancaster JR Jr. A tutorial on the diffusibility and reactivity of free nitric-oxide. Nitric-oxide. 1997; 1: 18-30.
(16.) Dale N, Roberts A. Dual-component amino-acid-mediated synaptic potentials: excitatory drive for swimming in Xenopus embryos. J Physiol. 1985; 363: 35-59.
(17.) Alkadhi K, Al-Hijailan R, Malik K, Hogan Y. Retrograde carbon monoxide is required for induction of long-term potentiation in rat superior cervical ganglion. J Neurosci 2001; 21 (10): 3515-20.
(18.) Kato K, Zorumski C. Platelet-activating factor as a potential retrograde messenger. J Lipid Mediat Cell Signal 1996; 14 (1-3): 341-8.
(19.) Hwang SJ, O'Kane N, Singer C, Ward SM, Sanders KM, Koh SD. Block of inhibitory junction potentials and TREK-1 channels in murine colon by Ca2+ store-active drugs. J Physiol. 2008; 586: 1169-1184.
(20.) Dutar P, Nicoll RA. A physiological role for GABAB receptors in the central nervous system. Nature. 1988; 332: 156-158.
(21.) Batchelor AM, Garthwaite J. Frequency detection and temporally dispersed synaptic signal association through a metabotropic glutamate receptor pathway. Nature. 1997; 385: 74-77.
(22.) Hallak JE, Maia-de-Oliveira JP, Abrao J, et al. Rapid improvement of acute schizophrenia symptoms after intravenous sodium nitroprusside: a randomized, double-blind, placebo-controlled trial. The Journal of the American Medical Association 70 (7): 668-676.
(23.) Zhang Y W, Gesmonde J, Ramamoorthy S, Rudnick G. Serotonin transporter phosphorylation by cGMP-dependent protein kinase is altered by a mutation associated with obsessive compulsive disorder. J Neuroscience. 2007a; 27: 10878-10886.
(24.) Chanrion B, Mannoury la Cour C, Bertaso F, Lerner-Natoli M, Freissmuth M, Millan MJ, Bockaert J, Marin P. A physical interaction between the serotonin transporter and neuronal NO synthase underlies reciprocal modulation of their activity. Proc Natl Acad Sci. USA. 2007;104: 81198124.
(25.) O'Dell T J, Hawkins R D, Kandel E R, Arancio, O. Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric-oxide as a possible early retrograde messenger. Proc Natl Acad Sci. USA. 1991;88: 11285-11289.
(26.) Kreitzer A, Regehr W G. Retrograde signaling by endocannabinoids. Current Opinion in Neurobiology 2002;12 (3): 324-330.
(27.) Malenka R, Bear M. LTP and LTD: an embarrassment of riches. Neuron 2004;44 (1): 5-21.
(28.) Schrammel A, Behrends S, Schmidt K, Koesling D, Mayer B. Characterization of 1H-[1, 2, 4]oxadiazolo[4, 3-a]quinoxalin-1-one as a heme-site inhibitor of nitric-oxide-sensitive guanylyl cyclase. Mol Pharmacol. 1996 Jul; 50 (1):1-5.
(29.) Friederich, JA et al. Sodium Nitroprusside: Twenty Years and Counting. Anesthesia and Analgesia 81 (1): 152-162.
(30.) Goodman and Gilman's the pharmacological basis of theurapeutics 12th; 783;796.
(31.) Thomas JE and Rosenwasser RH. Preliminary report: initial observations on the safety and efficacy of intrathecal nitric-oxide donors for the treatment of refractory cerebral vasospasm and ischemia in humans. Neurosurgery. 1998; 43: 670.
(32.) Horn P, Vajkoczy P, Thome C, Muench E, Schilling L, Schmiedek et al. Intrathecal sodium nitroprusside improves cerebral blood flow and oxygenation in refractory cerebral vasospasm and ischemia in humans. STROKE, 31(5), 2000, pp. 1195-1196.
(33.) 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 Jan 1999;44 (1): 48-57.
(34.) Hallak JE, Maia-de-Oliveira JP, Abrao J, et al. Rapid improvement of acute schizophrenia symptoms after intravenous sodium nitroprusside: a randomized, double-blind, placebo-controlled trial. The Journal of the American Medical Association 70 (7): 668-676.
(35.) Zhang Y W, Gesmonde J, Ramamoorthy S, Rudnick G. Serotonin transporter phosphorylation by cGMP-dependent protein kinase is altered by a mutation associated with obsessive compulsive disorder. J Neuroscience. 2007a;27: 10878-10886.
(36.) Chanrion B, Mannoury la Cour C, Bertaso F, Lerner-Natoli M, Freissmuth M, Millan MJ, Bockaert J, Marin P. A physical interaction between the serotonin transporter and neuronal NO synthase underlies reciprocal modulation of their activity. Proc Natl Acad Sci. USA. 2007;104: 81198124.
(37.) Atalay B, Caner H, Cekinmez M, Ozen O, Celasun B, Altinors N. Systemic administration of phosphodiesterase V inhibitor, sildenafil citrate, for attenuation of cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery. 2006;59:1102-7.
(38.) Kanchan K Mukherjee, Shrawan K Singh, Virender K Khosla, Sandeep Mohindra, Pravin Salunke. Safety and efficacy of sildenafil citrate in reversal of cerebral vasospasm: A feasibility study. Surg Neurol Int. 2012
(39.) Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke. 2002;33: 2675 80.
(40.) Dierckx RA, Peters O, Ebinger G, Six R, Corne L. Intraarterial sodium nitroprusside infusion in the treatment of severe ergotism. Clinical Neuropharmacology Feb 1986;9 (6): 542-548.
(41.) Carliner N, Denune DP, Finch CS Jr, Goldberg LI. Sodium nitroprusside treatment of ergotamine-induced peripheral ischemia. Journal of the American Medical Association Jan 1974;227 (3): 308-309.
(42.) Lewis PJ, Noseworthy TW, Fitzgerald AA, Andrews GC, Geeraert AJ. Rapid reversal of ergotamine-induced vasospasm. The Canadian Journal of Neurological Sciences Feb 1986;13 (1): 72-74.
(43.) Merhoff, GC; Porter, JM. Ergot intoxication: historical review and description of unusual clinical manifestations. Annals of Surgery Nov 1974;180 (5): 773-779.
(44.) Leonard F. Hirsh. Intra-Arterial Nitroprusside Treatment of Acute Experimental Vasospasm in dogs. Stroke, Vol 11, No 6, 1980.
(45.) Kondo T, Brock M, Bach H. Effect of intra-arterial sodium nitroprusside on intracranial pressure and cerebral autoregulation in cats. Jpn Heart J.1984;25 (2):231-7.
(46.) Joshi S, Young WL, Duong H, et al. Intracarotid nitroprusside does not augment cerebral blood flow in human subjects. Anesthesiology. 2002; 96: 60-66
(47.) Leif Henriksen, Olaf B. Paulson. The effects of sodium nitroprusside on cerebral blood flow and cerebral venous blood gases. European Journal of Clinical Investigation;12;5, 389-393, ;1982
(48.) Alger BE. Retrograde signaling in the regulation of synaptic transmission: focus on endocannabinoids. Prog Neurobiol 2002. 68 (4): 247-86.
(49.) Wilson RI, Nicoll RA. Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 2001;410 (6828): 588-92.
(50.) Holscher C. Nitric-oxide, the enigmatic neuronal messenger: its role in synaptic plasticity. Trends Neurosci. 1997;20: 298-303.
(51.) Prast H, Philippu A. Nitric-oxide as modulator of neuronal function. Prog. Neurobiol. 2001;64: 51-68.
(52.) Susswein AJ, Katzoff A, Miller N, Hurwitz I. Nitric-oxide and memory. Neuroscientist. 2004;10: 153-162.
(53.) Daniel H, Levenes C, Crepel F. Cellular mechanisms of cerebellar LTD. Trends Neurosci. 1998;21: 401-407.
(54.) Matthias Spranger et al. Superoxide Dismutase Activity in Serum of Patients with Acute Cerebral Ischemic Injury; Correlation With Clinical Course and Infarct Size. Stroke. 1997; 28: 2425-2428 doi: 10.1161/01.STR.28.12.2425
(55.) Steenblock D. Review of Hyperbaric Oxygen for Stroke Rehabilitation. Explore!; 7;5, 1996/97.
(56.) J Bamford, P Sandercock, M Dennis, C Warlow, J Burn. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 337 (8756): 1521-6.
(57.) Burgin WS, Malkoff M, Felberg RA, Demchuk AM, Christou I, Grotta JC, et al. Transcranial Doppler ultrasound criteria for recanalisation after thrombolysis for middle cerebral artery stroke. Stroke 2003; 31: 1128-32.
(58.) Alexandrov A, Demchuk AM, Wein T H, Grotta JC. Yield of Transcranial Doppler in Acute Cerebral Ischemia. Stroke. 1999 Aug; 30 (8):1604-9.
FIGURE 1A: SHOWS THE NORMAL REGULATION OF ANTEROGRADE NEUROTRANSMISSION BY NITRIC OXIDE AND IN VARIOUS ABNORMAL CONDITIONS WELL SUPPORTED BY VARIOUS PAPERS.
[FIGURE 1A OMITTED]
FIGURE 1B: SHOWS THE MECHANISM OF ACTION OF NITRIC OXIDE AT THE SYNAPSE LEVEL.
[FIGURE 1B OMITTED]
TABLE 1; CRITERIA FOR USE OF ICSNP IN TREATING ACUTE ISCHEMIC STROKE: CLINICAL INCLUSION CRITERIA:
1. Patient / caregiver able to give informed written and vedio recordings consent before and Vedio recordings after the study procedure.
2. Age >= 18years
3. Onset of symptoms of ischemic stroke from 3rd poststroke day to more than 7 days.
4. Measurable neurological deficit defined as impairment of language, motor function, cognition and/or gaze, vision or neglect, comprehension.
5. Score of Stroke severity >= 4 on the National Health Stroke Scale (NIHSS).
CLINICAL EXCLUSION CRITERION:
1. Minor stroke symptoms (NIHSS score <4) or those that are rapidly improving.
2. Patients fit for rTPA thrombolysis (3 hrs for anterior and 6 hrs for posterior circulation).
3. Seizure at onset unless the treating physician is convinced that the neurological deficit is due to stroke and not due to seizure.
4. Previous known intracranial hemorrhage.
5. Hemorrhage in pretreatment CT scan of the brain.
6. Uncontrolled baseline hypertension (>180/110).
7. Myocardial infarction in past 30 days.
8. Recent (<1 days) surgery, major arterial puncture, trauma or ulcerative wounds.
9. Known and clinical evidence of chronic or acute hepatic or renal disease.
10. Known bleeding diathesis/coagulopathies.
11. Patients on anticoagulants.
12. Pregnancy, lactation and parturition within previous 30 days.
13. Hypoglycemia, hyperglycemia (baseline serum glucose level must be between 50mg%-400mg%).
COMPUTED TOMOGRAPHY (CT) OR MRI (MAGNETIC IMAGING) EXCLUSION CRITERIA:
1. Evidence of acute or chronic intracranial bleeding on CT.
2. Likely etiology other than acute brain ischemia.
[FIGURE 3 OMITTED]
[FIGURE 4 OMITTED]
[FIGURE 5 OMITTED]
Consultant Neurosurgeon, Department of Neurosurgery, Neuro Center.
Consultant Neurosurgeon, Department of Neurosurgery, Neuro Center.
H. K. Das Gupta
Consultant Surgeon, Department of Neurosurgery, Neuro Center.
Consultant Cardiologist, Neuro Center.
NAME ADDRESS EMAIL ID OF THE CORRESPONDING AUTHOR:
Dr. Vinod Kumar Tewari, Director, Neuro Center, Lucknow-226010 U. P, India.
Date of Submission: 03/05/2014.
Date of Peer Review: 04/05/2014.
Date of Acceptance: 17/05/2014.
Date of Publishing: 26/05/2014.
TABLE 2 CLINICAL PRETREATMENT CHARACTERISTICS Age 63.75 years (45 to 72) Sex M:F 13:5 MEAN DAYS OF ICSNP 9.5 (RANGE 3 TO 22 DAYS) HYPERTENSION 72 (100%) DIABETES MELLITUS 36 (50%) HYPERCHOLESTEROLEMIA 72 (100%) AF NIL CHF NIL CAD 28 (38.88%) PRIOR INFARCT 4 (5.5%) SMOKING 68 (94.44%) MEAN ADMISSION BP 170/98 mm of Hg MEAN MAXIMUM PRETREATMENT BP 182/100 mm of Hg MEAN BASELINE NIHSS Mean 21.11 (range 10 to 33) TCD IMMEDIATE IN EMERGENCY ROOM TABLE 3: CLINICAL BASELINE NIHSS AND CHANGES NIHS CASES ICSNP score 82 Pts NIHSS Cases (Day) Baseline ICSNP 5 TO 15 12 10 11 (72/82) 16 TO 20 24 12.16 18.33 21 TO 42 36 6.55 28.33 Control NO 5 0 19.14 (10/82) Injection Dex 5% 5 15 20.2 Injection POST IT SNP NIHS SCORE BARTHAL'S CASES 1.30 2 24 7 2 SCORE 82 Pts NIHSS MINTS HOURS HOURS DAYS MONTHS 2 MONTHS ICSNP 5 TO 15 8.66 7.66 8 3 1.33 85% (72/82) 16 TO 20 16.16 14.66 15.66 4.66 2.83 88.33% 21 TO 42 25 23.33 24.11 5.33 3.25 72.5% Control NO 19.4 19.4 18.4 13.2 10.75 60% (10/82) Injection Dex 5% 20.2 20.2 19.8 17.2 14.2 65% Injection TABLE 4: BAMFORD'S CLASSIFICATION AND CHANGES AFTER ICSNP NIHS CASES ICSNP score 82 Pts BAMFORD'S Cases (Day) Baseline ICSNP LACS 12 6.33 13.33 (72/82) POCS 8 20 13.5 PACS 36 8.11 23.4 TACS 16 9.75 30 Control NO 5 0 19.14 (10/82) Injection Dex 5% 5 15 20.2 Injection POST IT SNP NIHS SCORE BARTHALS CASES 1.30 2 24 7 2 SCORE 82 Pts BAMFORD'S MINTS HOURS HOURS DAYS MONTHS 2 MONTH ICSNP LACS 10 7.66 9.33 3.66 2 85 (72/82) POCS 13 13 12.5 5 2 85 PACS 20.5 19.22 20 4.88 3.11 80.55 TACS 26.7 24.75 25.5 5 3 71.66 Control NO 19.4 19.4 18.4 13.2 10.75 60% (10/82) Injection Dex 5% 20.2 20.2 19.8 17.2 14.2 65% Injection
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||ORIGINAL ARTICLE|
|Author:||Kumar, Vinod; Husain, Mazhar; Gupta, H.K. Das; Singhvie, Ravi|
|Publication:||Journal of Evolution of Medical and Dental Sciences|
|Date:||May 26, 2014|
|Previous Article:||Pregnancy with carcinoma cervix.|
|Next Article:||Epidemiological study of poisoning cases in coastal Andhra Pradesh.|