Another study on critically ill septic patients assessed the possibility to characterize the asso­ciated brain dysfunction by measuring a static parameter obtained by Doppler ultrasound of the middle cerebral artery [14]. Cerebral endo­thelial cells are involved in the process of gen­eral inammation that characterizes sepsis and are activated early during the rst phase of the disease. This activation causes the release of pro- inammatory cytokines and nitric monox­ide in the brain, as already said, but also edema, platelet accumulation, and other mechanisms, all together causing impairment of microcirculation. Hypoxia is the nal result of these phenomena

and represents the main mechanism of brain dam­age. These alterations are characterized by the decrease in density of the microvessels regularly perfused, the main determinant of inadequate oxygen supply. Hypoxia is mechanically the result of the increase in the distance between the neurons and the capillaries [11]. The increase in vascular resistance of the capillary bed explains the decrease of density of perfused capillaries. Ultrasound has the power to assess the cerebral vascular resistance by measuring the pulsatility index, obtained by measuring the blood veloc­ity at the level of the middle cerebral artery by transcranial Doppler. The measurement of blood velocity at this level by transcranial Doppler can be considered an open window on the evalua­tion of cerebral blood ow and changes in time of this velocity represent a surrogate to predict the regional hemodynamic changes mediated by cerebral microcirculation [15]. It is largely dem­onstrated that an increase in the resistance to the blood ow distal to the site of insonation is char­acterized by an increase in blood ow pulsatil­ity [16]. Thus, pulsatility positively correlated to change in vascular resistance due to the change in tone and caliber of the peripheral small arteries. To obtain the pulsatility index, the middle cere­bral artery is visualized by scanning through the temporal bone window and measuring the blood velocity for 10s [14]. Measurements can be done on both sides of the skull and the highest mean velocity is considered valid. The pulsatility index is calculated as (Systolic velocity − Diastolic velocity)/Mean velocity (see Table 11.1). It is a static parameter that, when increased, dem­onstrates microcirculation disturbances that are signicantly related to clear clinical signs of sepsis-associated brain dysfunction. High values of pulsatility index over 1.3 measured at the very rst approach (within 24h) after the initial symp­toms of sepsis indicate the impending damage and occurrence of brain dysfunction [14]. Indeed, increased static pulsatility index as a sign of dif­fuse intracranial microcirculation disease may be found even in patients with stable hemodynam­ics. In sepsis however, only the increase in the very early phase was correlated and considered predictive of functional cerebral alterations and

severe prognosis [14]. This observation paves the way to the possibility that an early evaluation of the vascular resistance at the level of the cerebral microcirculation, via the calculation of the pul­satility index obtained by Doppler ultrasound of the middle cerebral artery, may make more ef­cient the initial diagnostic assessment and serve as a good prognostic indicator in severe sepsis. Furthermore, because sepsis is a dynamic state and has a systemic multifaceted characteristic, using the assessment of the pulsatility index dur­ing the time course of the disease may have the power to predict the response to treatment and be used as a sign of worsening, independent even from the assessment of the hemodynamic state. Increase of the pulsatility index may be a sign of increase in the cerebrovascular resistance and onset of autoregulatory disturbances, which may lead to exposure of the brain of the septic patient to reduction of cerebral blood ow. Thus, in clinical practice, the initial assessment and moni­toring of the pulsatility index may become a rst­line bedside technique in the early diagnosis and follow- up of critically ill septic patients.

There are limitations to the conclusion of studies on transcranial Doppler ultrasound in sepsis. First, the techniques of transcranial Doppler ultrasound here described consider the evaluation of blood ow at the level of a large intracranial artery, that is, the middle cerebral artery. Even if the assessment of blood ow at this level represents a predictor of the condi­tion of the microcirculation, it is only an indirect evaluation and cannot be fully representative of the real impairment of microcirculation that may lead to regional isolated and not diffuse ischemia consequences. Indeed, the mean ow index and the pulsatility index are mathematical simplica­tion of the complex biological phenomenon, that is, cerebral vascular autoregulation.

A promising bedside noninvasive tool to mon­itor brain dysfunction in liver failure is the tran­scranial Doppler. Intracranial pressure inuences the pattern of the cerebral blood ow velocity waveform assessed by ultrasound at the level of the middle cerebral artery [23]. In literature, only very few original studies demonstrated the power of transcranial Doppler in the prediction of intracranial hypertension in acute liver failure. Some of the evidence we may extract from litera­ture is based on case series. The mean cerebral blood ow was reduced and the pulsatility index increased in a series of patients with acute fail­ure from viral hepatitis [24–26]. In these studies, the transcranial Doppler pattern was demonstra­tive of hypoperfusion when compared to normal patterns. Thus, from this experience it seems that hypoperfusion of the cerebral vascular bed is the main factor that should be corrected by increas­ing cerebral perfusion and treating hypoxia. This data was conrmed by a specically designed original study on acute-onset end-stage liver fail­ure patients who were examined by transcranial Doppler of the middle cerebral artery to measure systolic, diastolic, and mean blood ow veloci­ties and pulsatility index [27]. This small study conrmed that the most frequent pattern in these patients was low ow and high resistance with high pulsatility index (see Table11.1). This com­bination was more signicant in the subgroup of patients who died. The high pulsatility index is considered a marker of increased intracranial pressure, in agreement with previous literature produced by studying other diseases [28–30]. In patients with acute liver failure this data is con­rmed, and high pulsatility index can be used as a sign of intracranial hypertension and worse prognosis.

transcranial Doppler indicating initial increase in the blood ow and cerebral vasodilation may justify the progressive increase in the intracranial pressure. From the moment cerebral vasodilation is rst detected onwards, the cerebral hemody­namics continue to deteriorate, and this is dem­onstrated by a progressive increase of intracranial pressure, concomitant signs of vasoparalysis of the cerebral vessels, and loss of autoregulation. In a condition of intracranial hypertension, vaso­paralysis is due to the increase in the extramural pressure due to cerebral swelling that, at the nal stage, may bring to Doppler evidence of sharp systolic peak and retrograde ow [32]. However, even if this detailed analysis of the waveform was nd to correlate with the evolution of the increase of intracranial pressure and changes in the hemo­dynamics of the cerebral vessels, it should also be considered that the intracranial hemodynam­ics is subjected to complex interactions, includ­ing the effect of temperature, systemic arterial pressure, and PaCO2 and their uctuations [33]. Thus, such a detailed quantitative analysis of the waveform may oversimplify a complex phe­nomenon that needs the consideration of a more complex model to be read and interpreted. The consideration of pulsatility index simplies the assessment. It is an index easy to calculate, less inuenced by the correct angle of insonation, and is more accurate in expressing the combination of many factors affecting the cerebral blood ow. However, this index represents a good picture of the resistance of the cerebral microcirculation but is not enough detailed to allow the analysis of the dynamic changes in the compliance of arterial vessels under the effect of the cerebral swelling and progressive increase of the intracranial pres­sure [33, 34]. A combination of the simple pul­satility index, which looks at the extrema in ow velocities, and a rough analysis of a few features of the linearized Doppler ow waveform may be more promising [31]. These latter analyses may be centered to the evaluation of the Windkessel effect, that is, the reduced blood vessel elastic­ity demonstrated by reduced elastic rebound of the cerebral vasculature (see Table11.1) [31, 32].