The present invention related to a non-invasive apparatus and method of threating cerebral ischemia or trauma. In particular, the invention involves the use of non-inhaled, intra-nasally or intra-orally delivered CO2 to augment cerebral perfusion and improved outcome following stroke.
Stroke occurs when focal cerebral ischemia is severe, prolonged or both. Cerebral perfusion augmentation early in the ischemic event improves outcome from stroke. One method to accomplish this is to elevate blood pressure but this carries the risk of cerebral hemorrhage. Furthermore, pharmacologic hypertension triggers autoregulatory responses and may actually reduce cerebral perfusion.
Pharmacologic manipulation of cerebral vascular tone has also been attempted using systemic vasodilators such as nitroprusside and nitroglycerin. Nitroprusside is a potent vasodilator but marked systemic hypotension overrides any beneficial effect it might have on the cerebral circulation. It has even been given concomitantly with vasoconstrictors such as epinephrine, but the latter leads to constriction of the cerebral vasculature. These complicated pharmacodynamics have prevented systemic hypotensive agents being used in the treatment of cerebral ischemia.
Several devices have recently been used to augment perfusion to the ischemic tissue. Clot retraction or thrombectomy, using a variety of devices, is used to remove the clot occluding the artery but the technique is associated with higher hemorrhage rates in the core, especially in patients treated beyond the first few hours of ischemia. Furthermore, vessel occlusion is not present angiographically in many patients. For all these reasons, thrombectomy is performed in fewer than 1% of strokes.
Partial aortic occlusion has also been shown to increase cerebral perfusion during ischemia when performed early and is not associated with increased cerebral hemorrhage rates. It is however, an invasive procedure requiring trained personnel. Vagal nerve stimulation may improve outcome from stroke in animals but has not been shown to do so in humans. The mechanism of action has not been elucidated though it may involve a dampening of the inflammatory cascade rather than an increase in cerebral blood flow (cbf). Electrical stimulation of the sphenopalatine ganglion, the ganglion for intracranial parasympathetic fibres, may also increase cbf but its benefit in stroke has not yet been determined and furthermore, like all other existing stroke treatments, it is an invasive procedure performed by interventional neuroradiologists.
None of the foregoing methods have been effective in improving the outcome from stroke. Further, the foregoing methods attempting to improve the outcome following stroke are invasive procedures requiring trained personnel. Thus, improvements over conventional therapies are desirable.
The present invention relates to a new non-invasive method of treating cerebral ischemia, involving the use of non-inhaled, intra-nasally delivered carbon dioxide (CO2), alone or in combination with other gases to augment cerebral perfusion and improve outcome following a stroke.
Intranasal delivery of CO2 focally for prolonged periods of time and without systemic absorption for improving outcome from cerebral ischemia has not been previously described. This procedure is completely non-invasive and avoids complications of gas inhalation.
The vasodilator gas alone or in combination with a second gas is delivered intranasally for prolonged periods of time without systemic absorption. The second gas is selected from the group consisting of NO, hydrogen, xenon, anesthetic gases, oxygen, nitrogen, nitrous oxide, carbon monoxide, or air. The treatment selectively increases cerebral perfusion and provides neuroprotection in the treatment of cerebral ischemia.
For a better understanding of the invention, and to show how the same may be carried into effect, reference will now be made, by way of example, to the accompanying drawings, in which:
As used herein, cerebral ischemia should be understood in its broadest sense and incorporate both focal and global cerebral ischemia.
Intranasal delivery of CO2 focally for prolonged periods of time and without systemic absorption for improving outcome from cerebral ischemia has not been previously described. This procedure is completely non-invasive and avoids complications of gas inhalation.
The vasodilator gas alone or in combination with a second gas is delivered intranasally for prolonged periods of time without systemic absorption. The second gas is selected from the group consisting of hydrogen, xenon, anesthetic gases, oxygen, carbon monoxide, or air. The treatment selectively increases cerebral perfusion and provides neuroprotection in the treatment of cerebral ischemia.
Puffs of CO2 have been given intranasally to ameliorate allergic rhinitis and migraine symptoms, possibly through trigeminal stimulation (U.S. Pat. No. 7,748379). These patients must cooperate and be trained to not inhale through their nose during treatments which only lasts a few seconds. In such tiny doses lasting only seconds, only very small amounts of CO2 will in fact be inhaled and systemic effects of this inhalation will be negligible. However, if the CO2 treatment period exceeds this short time, and continues for 30-60 minutes as envisaged in this filing, then inhalation of CO2 will be manifest and systemic arterial gas and pH changes be evident, as will the physiological consequences of CO2 inhalation. What we are proposing to do is different. We will be delivering the vasodilator gas alone or in combination for prolonged periods of time without any systemic absorption and for selectively increasing perfusion in the treatment of cerebral ischemia.
Systemically delivered CO2 gas is a very potent cerebral vasodilator. In intubated patients, when CO2 is allowed to rise by reducing the ventilation rate, cbf rises rapidly and linearly in response to hypercarbia, such that every mm Hg increase in arterial CO2 over 45 mm is associated with a 4% increase in cbf. CO2 is very soluble and diffuses readily through the blood brain barrier (BBB) and from the intravascular space intracranially to the cerebrospinal fluid (csf). The mechanism of action is through formation of hydrogen ions which then stimulate nitric oxide formation in cerebral vessels. Hydrogen ions also stimulate the chemoreceptor trigger zone (CTZ) in the anterior medulla which leads to neurogenic vasodilation.
When CO2 s inhaled through the nose or mouth into the pulmonary circulation, it passes into the systemic blood stream through the alveoli. Once it reaches the brain, it diffuses out into the csf to exert its effect. As more CO2 is inhaled into the lungs and absorbed into the systemic circulation, arterial CO2 concentration (PaCO2) rises, hydrogen ions are produced and arterial pH falls, creating an acidosis. Acidosis leads to narcosis, and ultimately coma and death. Less severe signs of CO2 inhalation in non-intubated patients include headaches, sweating and hyperventilation. We have demonstrated that CO2 augments cbf when delivered intranasally but without inhalation into the lungs in the rat as illustrated in
Referring now to
As can be seen in
The volumes of CO2 delivered intra nasally and without inhalation to achieve an increase in cbf are very small compared to those required to produce the same amount of cbf increase by inhalation into the systemic circulation. Because of this, the acidosis and ultimate stupor , coma and death which would occur following CO2 inhalation would not occur if CO2 were delivered focally into the nose, close to the cerebral circulation and without the need for inhalation.
Assuming a minute volume of 6 liters per minute and a 50 mL per minute flow of 16% CO2 into the nasal cavity, if all the CO2 is inhaled, the effective increase in alveolar CO2 would be 0.13% or 1 mmHg which would have practically no effect on arterial pH.
Referring now to
While CO2 may be given to intubated, comatose individuals, the tolerability of intranasal gas delivery in awake humans has not previously been investigated. We have systematically tested the tolerability and effect of CO2 during intranasal delivery. Results are shown in
In yet another embodiment, CO2 could be delivered with another vasodilator drug in topical ointment form, such as glyceryl trinitrate. The ointment and the CO2 gas could enhance each other's absorption across the nasal mucosa.
CO2 may also affect the outcome from cerebral ischemia or trauma by mechanisms other than cbf augmentation. More specifically, it might have a neuroprotective action of its own when delivered intranasally, rather than by inhalation. The mechanism of action might be inhibition of glutamate/NMDA-mediated excitotoxicity or by caspase/interleukin/TNFalpha-mediated inflammation later in the course of the insult. Neuroprotection with systemic hypercarbia (following CO2 inhalation or hypoventilation) may be available even when inhaled for only 2 hours.
In yet another embodiment, CO2 could be delivered with another neuroprotective gas such as carbon monoxide. Carbon monoxide (CO) may also be neuroprotective following ischemic or traumatic injury.
As best seen in
The combination of CO2 and of other gases might have a synergistic effect on cbf. Furthermore, this would permit further reduction in the concentrations or volumes required to achieve the same effect.
Referring to
Volatile anesthetics, arginine and other gases such as hydrogen, and other gases known to those skilled in the art, may also stimulate the trigeminal nerve and the autonomic fibres travelling with it, when delivered as gases into the nasal or oral cavity without being inhaled. Any one of these could be given alone or in combination with CO2 to improve outcome from cerebral ischemia.
Lastly, non-inhaled CO2, alone or in combination, might be useful for the treatment of transient ischemic attacks (TIA) and vasospasm. In the case of TIA, a separate embodiment would be used outside a hospital setting. In this embodiment, the CO2 would be in an inhaler, and the gas release would only occur once the nasal plugs were properly positioned. This embodiment could also be used to increase cerebral blood flow transiently, when attention or memory needed to be improved. Cerebral blood flow diminishes with age and the elderly could benefit from periodic boosts.
Various modifications and additions may be made to the exemplary embodiments disclosed herein without departing from the scope of the invention. For example, while the embodiments disclosed herein refer to particular features, the scope of this invention also includes embodiments having different combinations of features and embodiments that do not include all of the described features. Accordingly, the scope of the present invention is intended to embrace all such alternative, modifications and variations as fall within the scope of the claims and equivalents thereof.
This application claims the benefit of priority to U.S. Appln. Ser. No. 61/624,484 filed on Apr. 16, 2012 and U.S. Appln. Ser. No. 61/661,709 filed on Jun. 19, 2012 and U.S. Appln. Ser. No. 61/720,164 filed on Oct. 30, 2012, the entireties of which are hereby incorporated by reference.
Number | Date | Country | |
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61624484 | Apr 2012 | US | |
61661709 | Jun 2012 | US | |
61720164 | Oct 2012 | US |