In a previous phase 1 trial, it was observed that CBF can be reproducibly increased by intermittent controlled hypercapnia in the days following aneurysm rupture in patients with poor grade SAH (10, 6). In that trial, CBF increased during a sequential increase of arterial PaCO2. After resetting mechanical ventilation to baseline parameters, CBF showed a slow and asymptotic return to starting levels without a negative rebound effect. This observation suggested that a longer duration of hypercapnia might even extend the CBF-increasing effect. The present study was planned as a dose optimization study in order to identify the time-point at which CBF reaches a maximum. It was assumed that after a maximum CBF increase upon elevated PaCO2, buffer mechanisms in blood and CSF may result in adaptation mechanisms that lead first to an attenuation of the CBF-increasing effect and then to a negative rebound effect after the hypercapnic challenge is terminated. For safety reasons, a preliminary termination of the study intervention was included into the study protocol if the CBF-enhancing effect secondarily declined by more than 25%. In order to identify the time-point of the maximum intrinsic effect of controlled hypercapnia upon the cerebral vasculature, the value was corrected by the possible inotropic effect of prolonged hypercapnia which has been described previously (11). Indeed, a positive inotropic effect was also noted during the study interventions conducted in this present study, moderate but statistically significant. It resulted in a “net” optimum effect of the hypercapnic challenge on the cerebral vasculature of 45 minutes. After the proof of principle in a previous study and the present results we suggest that this may be the basis for an evaluation of efficacy in a controlled clinical trial.
Aneurysmal SAH is still a life-threatening incident with poor over-all prognosis. Its course is characterized by serially occurring ischemic events. Immediately after the rupture of the aneurysm, cerebral perfusion pressure (CPP) decreases due to a sudden increase of ICP resulting in a reduction of CBF and global ischemia. Simultaneously or shortly thereafter, diffuse early arterial vasoconstriction has been observed and contributes to the persistent perfusion deficit in the early stage of SAH (12, 13). Due to developments in emergency care, an increasing number of patients with poor-grade SAH can be adequately resuscitated and find their way to a specialized unit. Patients in a poor clinical condition and large amounts of blood in the subarachnoid space, in turn, are prone to develop vasospasm and delayed cerebral ischemia. To date, no single drug or manipulation has proven undoubtedly effective to prevent or treat the risk for DCI. Even the evidence for nimodipine, the most widely used pharmacological attempt to prevent DCI is based on a single trial which was conducted more than 30 years ago before endovascular aneurysm and vasospasm therapy was invented and without intensive care therapy with contemporary standards (14, 15).
Delayed vasospasm after a few days, caused by endothelial dysfunction, structural changes of the vessel wall, and inflammatory processes is likely to be an important factor for delayed ischemic neurological deficits (DIND) and delayed cerebral ischemia (DCI) (16, 17). A variety of clinical and experimental studies have investigated various approaches to prevent vasospasm (14, 18, 19, 20). But even initially promising trials, e.g. with endothelin A receptor antagonists, successful in treating vasospasm, did not prevent DCI or improve clinical outcome (21).
Most likely, DCI is a multifactorial phenomenon with delayed cerebral vasospasm, cortical electrical hyperactivity with enhanced energy expenditure, disturbed equilibrium of local vasodilatory and vasoconstrictive paracrine factors and a possible primary metabolic derangement contributing to ischemic damage. However, these factors finally turn into a common finish line, the mismatch of oxygen supply and demand of brain tissue resulting in a breakdown of aerobic metabolism, depletion of energy stores and terminal depolarization of neurons and glial cells.
From a pathophysiological point of view, delayed ischemia after SAH is a slowly arising perfusion deficit rather than a sudden and complete ischemia. Energy depletion, therefore, is also likely to be gradual. Thus, the rationale behind intermittent controlled hypercapnia is to temporarily increase a critically reduced CBF so that energy stores can recover.
It has long been shown that cerebral autoregulation of arterial blood pressure is disturbed after severe aneurysmal SAH and that the equilibrium of local factors are shifted towards constriction. However, the reactivity to changes of PaCO2 remains vital (2, 3, 22, 23). Increased PaCO2 may not have an effect on CBF and vessel diameter in the early stage of SAH as recently published by Friedrich and co-workers (24). For the chronic phase, however, previous work has shown a highly reproducible increase of StiO2 and CBF under staged hypercapnia. Since this effect was still reproducible during angiographically proven vasospasm (6) the concept of maximum peripheral vessel dilation downstream of large-trunk vasospasm may have to be rethought. At the same time, it gives space for a therapeutic intervention. A previous phase 1 study has not only shown the proof of principle without noteworthy negative side effects, but also a surprising reduction of the incidence of DCI and relatively favorable outcome as compared to historical controls and data published in literature (6, 10).
The previous results make it seem worthwhile to evaluate this procedure regarding its therapeutic effect. However, to date no data about the ideal duration of hypercapnia on CBF and cerebral tissue oxygenation exists. From a physiological point of view these positive effects must be temporary since buffer mechanisms in blood and CSF, connected via the carboanhydrase enzyme, trigger an adaptation to long-term changes of CO2.To the best of our knowledge, there is no literature about the long-term effects of hypercarbia upon CBF and the course of its adaptation. From high altitude research it is known that mountaineers start to hyperventilate during ascent, which results in a decrease of CBF. After several hours or days, depending on the altitude, acclimatization processes are leading to a normalization of ventilation and physiological parameters (7, 8). However, this is not the timeframe of interest for the particular needs of our patient collective. In contrast to our study protocol the effects in high altitude and its impact on CBF do not occur in a range of seconds or minutes but rather within hours and days during or after and ascent. An additional factor is the lower partial pressure of O2 in high altitude leading to hypoxia; therefore, this data is not comparable with normoxic conditions on an intensive care unit. Adaptation mechanisms to long-term hypercapnia, e.g. buffer in the cerebrospinal fluid or blood via carboanhydrase are neither well known nor investigated in trials up to now. Alterations of the pH of the brains’ extracellular space as a regulator of the cerebrovascular response to CO2 were discussed by Lassen et al., but remained unproven (25). Raichle and co-workers examined the effects of transient hyperventilation for several hours on CBF in healthy volunteers covering the period that is of interest for our particular study setting. They showed that CBF decreased with the onset of hyperventilation, but gradually recovered again under continuous hyperventilation and finally exceeded baseline levels in terms of a rebound effect when ventilation was returned to normal. PaCO2 also decreased initially but remained constantly low under hyperventilation and returned to baseline parameters after ending of hyperventilation (26).
We assume that the time-course, extent and reaction upon adaptation to hypercapnia is approximately the same as the adaptation to hyperventilation as reported by Raichle et al. (26). This implies that in patients with SAH, whose CBF is critically reduced, there is the danger that a negative rebound effect may carry CBF below ischemic thresholds even if there is a beneficial effect during the study intervention. Therefore, the duration of CBF hypercapnia must not exceed a safe time-frame.
Previous data on the effect of graded hypercapnia after aneurysmal SAH (6) showed a sustained effect on CBF and StiO2 and no rebound effects or adverse events. In this present trial, under continuous hypercapnia of 50–55 PaCO2 for 120 minutes, CBF and StiO2 reached peak values after 75 minutes and 60 minutes, respectively. Hence, at first glance 60 to 75 minutes seem to be the ideal duration for the highest treatment benefit. Regarding the parallel increase of cardiac output under prolonged hypercapnia the results have to be corrected in order to calculate the maximum intrinsic effect upon cerebral vessels. As a result of disturbed cerebral autoregulation after SAH, systematic increase of cardiac output alone, e.g. via application of catecholamines, could lead to an increase in CBF. Adjusting CBF by cardiac output, the hypercapnia-induced net increase of CBF was highest as early as 45 minutes after the start of the trial intervention. Given the statistically significant elevation of cardiac output after 60 minutes with further increase under prolonged hypercapnia, sustained therapeutic hypercapnia after reaching its maximum effect on CBF seems not advisable; adaptation mechanisms and negative cardiac effects bear the danger of a negative rebound effect with a secondary decline of CBF below the starting level.