Can In Vitro Studies Be Reliably Extrapolated to In Vivo Behavior ?

To the Editor:—We read with interest the recent article by de Nadal et al., who carefully examined the influence of morphine and fentanyl on cerebral hemodynamics in patients with severe head injury. The authors reported that both opioids cause small and transient increases in intracranial pressure (ICP), regardless of the autoregulatory capacity of the patient. We agree that this is an important, heretofore considered settled, issue and believe that the work of de Nadal et al. adds to our understanding of the pharmacodynamics of opioids in this population of patients. However, there are methodologic issues in the study that require cautious interpretation. It is acceptable to use arteriojugular venous oxygen content difference (AVDO2) changes as a surrogate for cerebral blood flow changes, provided we accept that cerebral metabolic rate stays constant, and no intracerebral steal occurs during the study. However, given that all patients were studied subsequently with transcranial Doppler ultrasonography, why was autoregulation quantified only with AVDO2 measurements, and not with flow velocity measurements as well? Furthermore, during cerebral autoregulation testing, the authors corrected for change in arterial carbon dioxide tension (PaCO2) according to carbon dioxide reactivity, which is appropriate. However, the autoregulatory capacity is influenced by PaCO2, with hypocapnia improving it and hypercapnia impairing it. We assume the authors made an effort to control PaCO2, but it would be more informative if the authors would also tell us the actual PaCO2 present during autoregulation testing and whether this remained unchanged when opiates were administered. The more difficult issues relate to the arbitrary classification of autoregulatory pattern and the magnitude of mean arterial pressure (MAP) change caused by the doses of opioids given in this study. Cerebral autoregulation is not an all-or-none phenomenon, and there are different magnitudes of impairment. Nevertheless, we agree that it is useful to classify the responses into impaired or preserved to advance our understanding of pathophysiology and design better treatment regimens. The criteria of Enevoldsen and Jensen are useful. However, such arbitrary classification can cause problems with interpretation of the current data. Impaired autoregulation is not the same as abolished autoregulation. Therefore, a patient with impaired autoregulation can mount a vasodilatory response to a decrease in blood pressure, albeit not sufficient to restore cerebral blood flow fully. To which group should such a patient be assigned? Therefore, it is not surprising to observe a lack of difference between the two groups with respect to ICP changes in response to opioid administration. When examined as a group (figs. 2A and B), both morphine and fentanyl patients had only a small decrease in MAP (3–4 mmHg) and a similar small increase in ICP. These results differ markedly in magnitude of MAP change (. 10 mmHg) from the observations of Werner et al., who administered 3 mg/kg sufentanil, and, therefore, leave open the question of whether the hypothesis was tested adequately. Given the heterogeneous magnitude of autoregulation preservation present in either group (autoregulating versus nonautoregulating patients) and the small effect of the opioids on MAP observed for the doses given, it remains plausible that there was insufficient challenge to discriminate between the two groups on the basis of ICP response. It is possible, however, that de Nadal et al. have unmasked a subcomponent of the mechanistic basis of ICP responses to opioid administration. It can be speculated that, although the dose they administered was insufficient to challenge autoregulatory status, a coupled increase in blood flow attributable to cerebral activation by the drugs was seen. We respectfully submit that the influence of opioids on cerebral hemodynamics is an important issue, and the paper by de Nadal et al. has contributed substantively to our understanding of this subject. However, the data presented do not rule out the hypothesis that major opioid effects on ICP are attributable to autoregulatory responses to concurrent reduction in MAP.