Cerebral blood flow during and after cardiac arrest

As discussed in a previous post, perfusion of the brain following long-term (>5 min) ischemia has been shown to be significantly compromised, particularly in subcortical regions. An interesting recent article by Ristagno, et. al in Resuscitation (May 2008) has added new data to the equation, using some of the most advanced technologies available for measuring cerebral microvascular blood flow.

To briefly summarize the experiment, pigs were subjected to 3 minutes of untreated ventricular fibrillation followed by 4 minutes of cardiopulmonary resuscitation and subsequent defibrillation. Blood flow in large (>20 micrometers) and small (<20 micrometers) cerebral vessels was measured during and after CPR by direct visualization using orthogonal polarization spectral imaging (OPS) together with cortical-tissue partial pressure of carbon dioxide.

Though prior studies implied a dissociation between microcirculatory flow and macrocirculation during CPR, Ristagno, et. al found “a close relationship between microvascular flows and the macrocirculation during cardiac arrest, during CPR and following return of spontaneous circulation (ROSC).” Interestingly, they also noted that cerebral blood flow was reduced, but did not stop, for more than 2 minutes after cardiac arrest, most likely due to residual compliance in the arterial circuit. After ROSC, flow progressively increased back to normal (pre-arrest) values within 3 minutes.

Importantly, the researchers also noted that cerebral cortical-tissue partial pressure of carbon dioxide (a measure of the severity of cerebral ischemia) increased progressively througout CPR, providing evidence for the fact that the pressure and flow generated during chest compressions “may minimise but do not reverse the magnitude of the brain ischaemia which preceded the start of CPR.”

Though many investigations, such as the previously reported study by Fischer & Ames reported no-reflow or hypoperfusion following ischemia, these authors observed no such phenomena, possibly because of the short duration of cardiac arrest. Indeed, they ultimately conclude that “a 3-min interval of ischaemia was therefore probably not long enough to induce alterations in blood flow during reperfusion.” Also of importance is the fact that OPS technology limits visualization of microvessels to within 1mm of the cortical surface. However, this paper still gives us better insight into the immediate effects of cardiac arrest, cardiopulmonary resuscitation, and reperfusion on microcirculatory flow in the brain.

Sustained abdominal compression

Conventional CPR typically generates around one-third to one-fourth of normal cardiac output, which is not sufficient to meet cerebral energy demands. In cryonics patients, cardiac output may be further compromised because many patients are atherosclerotic and/or have gone through a prolonged period of shock / multiple organ failure prior to pronouncement of legal death. However, conventional chest compression techniques can be improved and augmented to produce higher cardiac output and cerebral blood flow.

In cryonics, chest compression techniques range from manual chest compressions to mechanical high impulse active compression-decompression cardiopulmonary support (CPS). A recent technology that has been introduced to cryonics is the use of a mechanical load-distributing band CPS device, the Autopulse. Cerebral blood flow can be further augmented by using a respiratory impedance valve (such as the ResQPOD) and administration of vasoactive medications, such as epinephrine and vasopressin.

Although these interventions can improve cerebral blood flow during CPS, it is a well documented fact that many cryonics patients do not benefit from such improvements. Administration of vasoactive medications requires intravenous access which is often difficult to obtain in the typical cryonics patient. Similarly, the use of an impedance valve requires a patent airway which requires rapid and successful intubation of the patient. Clearly, it would be beneficial to have a technology that can be rapidly applied, is non-invasive, and does not require special technical knowledge or manual skills.

Abdominal compression appears to be such a technology. An air-inflatable cuff is positioned on top of the abdomen and secured in place. In some versions of the technology, a contoured cuff follows the lower border of the rib cage to minimize the chance of interference of the cuff with lung inflation during positive pressure ventilation. Constant abdominal compression is achieved by inflating the cuff during chest compressions. Abdominal compression increases coronary and cerebral blood flow by a) increasing intrathoracic pressure, b) increasing functional arterial resistance, and c) redistributing blood volume above the diaphragm out of the abdominal compartment (in: Biomedical Engineering Fundamentals, 2006).

In a recent study by Lottes et al. (2007), sustained abdominal compression was able to raise coronary perfusion pressure as much as vasopressor drugs. Progressively better results were obtained when abdominal pressure was increased from 100 mmHg to 500 mmHg. Optimal results were obtained when abdominal compression was used in combination with vasopressor drugs. This technology has also been evaluated in humans; Chandra et al. (1981) reported increased mean arterial, systolic, and diastolic blood pressure during CPR following cardiac arrest in humans.

Advantages of sustained abdominal compression in cryonics include: low fabrication costs, light in weight, indefinite shelf life, no refrigeration requirements, no electrical power requirements, easy to apply, immediate onset of action, constant effect over time (unlike medications), and immediately reversibility of the procedure.

The disadvantages of sustained abdominal compression are not evident but warrant careful consideration: (a) Abdominal compression may exacerbate ischemia-induced abdominal hemorrhage – this disadvantage is highly speculative since rupture of the inner lining of the gastric mucosa is a biochemical, not mechanical, event. It is clear, however, that abdominal compression is contra-indicated in patients with abdominal swelling and related gastrointestinal complications. The band and cuff may also interfere with placing a gastric tube to administer an antacid (I owe this point to Stephen Van Sickle). (b) Reversal of abdominal compression may rewarm the upper part of the body as a result of warmer blood having increased access to the upper torso and brain – this, again, is speculative and depends on the question of whether abdominal compression induces selective cooling of the torso. If such a scenario is possible, this effect might be limited by not reversing compression until internal cooling is started. The question remains, however, if better perfusion of the brain will offset slower cooling of the brain as a result of decreased surface cooling. (c) The inflatable cuff may interfere with the Autopulse technology – it is not likely that the two technologies will interfere because the lower part of the Autopulse band does not come into contact with the upper part of the abdominal compression cuff.

Another concern that has been raised about using this technology in cryonics concerns the possibility that abdominal binding has the effect of shunting blood to the upper torso and brain. The resulting lack of perfusion, and subsequent collapse of the vascular bed in the lower extremities, may make raising and cannulating the femoral vessels very difficult, if not impossible. An opposite view is that abdominal compression may actually facilitate femoral cannulation because it creates a bloodless field and enhances visibility of the vein by inflating and distending it (I owe this point to Brian Wowk). It should also be noted that not all cryonics stabilization cases are followed by blood washout through the femoral vessels. Examples include remote cases without blood washout, local cases, and cases in which the patient is cryoprotected in the field (in which surgical access may be obtained through median sternotomy or the cerebral vessels).

It remains to be seen if sustained abdominal compression becomes more popular in resuscitation medicine. Provided this technology is as effective as documented in the Lottes paper, contemporary cryonics stabilization procedures may benefit from such a simple technology to increase blood flow to the brain during CPS.

Selected Bibliography

Lottes AE, Rundell AE, Geddes LA, Kemeny AE, Otlewski MP, Babbs CF.
Sustained abdominal compression during CPR raises coronary perfusion pressures as much as vasopressor drugs.
Resuscitation. 2007 Dec;75(3):515-24.

Wik L, Naess PA, Ilebekk A, Steen PA.
Simultaneous active compression-decompression and abdominal binding increase carotid blood flow additively during cardiopulmonary resuscitation (CPR) in pigs.
Resuscitation. 1994 Jul;28(1):55-64.

Babbs CF, Blevins WE.
Abdominal binding and counterpulsation in cardiopulmonary resuscitation.
Critical Care Clinics. 1986 Apr;2(2):319-32.

Koehler RC, Chandra N, Guerci AD, Tsitlik J, Traystman RJ, Rogers MC, Weisfeldt ML.
Augmentation of cerebral perfusion by simultaneous chest compression and lung inflation with abdominal binding after cardiac arrest in dogs.
Circulation. 1983 Feb;67(2):266-75.

Chandra N, Snyder LD, Weisfeldt ML.
Abdominal binding during cardiopulmonary resuscitation in man.
JAMA. 1981 Jul 24-31;246(4):351-3.

Systemic administration of L-Kynurenine

L-Kynurenine (L-KYN) is one of the neuroprotective agents used in cryonics stabilization protocol to limit injury to the brain after cardiac arrest. Administration of L-KYN was perceived to be essential to resuscitate dogs from extended periods (up to 17 minutes) of normothermic ischemia during the Critical Care Research (CCR) cerebral resuscitation experiments in the late 1990s. In cryonics L-KYN has been combined with another neuroprotective agent, niacinamide, to make the compound NiKy.

L-KYN is the precursor of kynurenic acid, the only known endogenous antagonist of the excitatory amino acid receptors. Unlike kynurenic acid, L-KYN can cross the blood brain barrier. Because in cryonics neuroprotective agents are administered to the systemic circulation, the effects of such molecules on blood pressure and cerebral blood flow must be weighed against the benefits as a neuroprotectant.

Katalin Sas et al. investigated the effect of systemic administration of L-Kynurenine on corticocerebral blood flow under normal and ischemic (unilateral carotid artery occlusion) conditions in conscious rabbits. Corticocerebral blood flow (cCBF) was measured using the hydrogen clearance technique (i.e., hydrogen polarography). The investigators observed a significant increase in cCBF for both normal and ischemic animals. In the ischemic animals systemic administration of L-KYN resulted in cCBF that approached or even exceeded the base values measured in the normal animals. Administration of L-KYN did not alter arterial blood pressure or heart rate and its effects were of long duration, peaking between 60 and 240 minutes after administration.

The experiments cannot answer the question of whether L-KYN itself or one of its derivatives (such as kynurenic acid) increases cCBF. Other NMDA receptor antagonists have been found to increase cCBF as well. The authors investigated the possibility that the increase of cCBF might be caused by activation of the ascending cholinergic pathways as a response to NMDA receptor antagonism and found that pre-treatment with atropine prevented the increase of cCBF by L-KYN. The authors also investigated the effect of pre-treatment with the non-specific nitric oxide synthase (NOS) inhibitor L-NAME and found that the increase of cCBF was blocked by this agent as well. This suggests that the L-KYN induced increase in cCBF may be mediated by NMDA antagonist induced NO production. A direct effect of L-KYN on cerebral vessels is doubtful because other studies using either glutumate, NMDA, or agonists and antagonists of the former, failed to affect the tone of isolated cerebral arteries.

If systemic administration of L-KYN enhances cCBF in humans as well, L-KYN might be an attractive agent to treat stroke and cardiac arrest due to its multimodal properties. The beneficial properties of L-KYN on cCBF, instead of (or in addition to) its properties as a neuroprotectant may explain its importance in the CCR cerebral resuscitation experiments. Unlike some neuroprotective agents used in cryonics, such as Propofol and Tempol, L-KYN does not appear to have adverse hemodynamic effects and even improves cerebral blood flow. Although the efficacy of kynurenine as a neuroprotectant in cryonics remains uncertain and investigations into the biochemical and temporal aspects of its metabolism (and the effects of rapid induction of hypothermia on this) are warranted, the drug cannot be ruled out because of adverse effects on blood pressure or cerebral blood flow.