Shock is a life-threatening disorder presenting a state of tissue hypoperfusion that is associated with high mortality (1, 2). Shock is a common condition in critical care, affecting about one-third of patients admitted to the intensive care unit (3). As proposed by Weil and Henning (4), shock can be defined as “an acute circulatory failure with signs of tissue hypoperfusion that are apparent through the three windows of the body” (5), including skin perfusion, urine output, and brain function (5). In fact, brain dysfunction is nowadays mostly observed as part of the multi-organ dysfunction syndrome in shock patients (5, 6)
Resuscitation with timely and appropriate management of shock should be targeting global and regional perfusion parameters such as arterial blood pressure (BP), capillary refilling time, and urine output (7), aiming to re-establish adequate systemic and organ perfusion, including brain perfusion (7–9). Under normal physiological conditions, brain perfusion is protected by the mechanism of cerebral autoregulation (CA), which maintains cerebral blood flow (CBF) relatively constant despite large changes in BP (10). Impairment of CA can lead to disturbances in CBF that could play a role in the occurrence of brain dysfunction during shock due to brain hypoperfusion (i.e., tissue hypoxia) or hyperperfusion (i.e., brain edema and capillary damage) (11). Furthermore, in patients with circulatory shock, disturbed CA may exacerbate the mismatch between cerebral oxygen and metabolic demand, leading to additional brain injury and worse short- and long-term outcomes such as delirium, cognitive decline, stroke and is independently associated with mortality (12, 13). Therefore, cerebral perfusion represents a physiologically based end-point in critical illness, which may allow individualized management of patients at risk of neurological damage (14).
Given the relevance of CA as a mechanism to protect cerebral perfusion, we tested the hypothesis that CA is impaired in critically ill patients with circulatory shock in comparison with healthy subjects and that this alteration would be associated with the severity of disease or organ dysfunction.
This observational study was performed at Hospital São Rafael, Salvador, Bahia, Brazil from July 2017 to May 2019. Patients were considered eligible to participate in the study if they were aged 18 years or older; in the absence of pre-existing cerebrovascular diseases and acute neurological symptoms (i.e., focal motor and/or sensitive deficit or seizures); they were diagnosed with circulatory shock. Shock was defined as: mean BP less than 65 mm Hg or systolic BP less than 90 mm Hg, despite adequate fluid resuscitation (i.e., at least 30 mL/kg of crystalloids); use of vasoactive drugs; signs of tissue hypoperfusion (i.e., altered mental state, mottled skin, urine output below 0.5 mL/kg for 1 h) and/or a serum lactate level ≥ 18 mg/dL). Control subjects with mild hypertension on medical therapy were included as representative of elderly healthy controls. The study was approved by the local research ethics committee (89544418.3.0000.0048).
Measurements and data analysis
The study was performed with participants lying in a supine position, with the head at 30°, by the same investigator. CBF velocity (CBFV) was measured with TCD in both middle cerebral arteries (MCAs) using bilateral 2-MHz pulsed range-gated probes (DWL, Dopplerbox, Germany) held in place with a head frame. Subjects with unilateral temporal acoustic window were excluded. Insonation depths varied from 50 mm to 55 mm, with slight anterior angulation (15°–30°) of the probe through the temporal window. BP was measured invasively with an arterial catheter (CARESCAPE B650, GE, Stockholm, Sweden) in the shock patients. In the healthy subject's group, the BP was continuously measured noninvasively using finger arterial volume clamping (Finometer PRO; Finapres Medical Systems, Amsterdam, The Netherlands). End-tidal CO2 was continuously measured with an infrared capnograph (CARESCAPE B650, GE, Stockholm, Sweden) via the endotracheal tube and recorded at 1-min intervals. End-tidal CO2 was not monitored in control subjects.
Signals were sampled at a rate of 100 Hz and stored on a dedicated personal computer for offline analysis. All recordings were visually inspected, and the BP signal was calibrated using the systolic and diastolic values of radial sphygmomanometry. Narrow spikes (<100 ms) and artifacts were removed by linear interpolation. Subsequently, all signals were filtered with a zero-phase eighth-order Butterworth low-pass filter with a cut-off frequency of 20 Hz. The beginning and end of each cardiac cycle were detected in the BP signal, and mean values of BP, CBFV, and heart rate were obtained for each cardiac cycle. Systolic, and diastolic values of blood flow velocities (CBFVs, and CBFVd, respectively) and the pulsatility index (PI = [CBFVs-CBFVd]/CBFVm) were then calculated (15). Beat-to-beat parameters were interpolated with a third-order polynomial and resampled at 5 Hz to generate signals with a uniform time base.
Dynamic CA was modeled using transfer function analysis, using spontaneous fluctuations of mean BP as input and corresponding changes in CBFV as output, as described previously (16, 17). The Welch method was adopted for smoothing spectral estimates obtained with the fast Fourier transform (102.4 s segments, 50% superposition). Using the inverse fast Fourier transform, the CBFV response to a step change in BP was also derived and compared with 10 template curves proposed by Tiecks et al. (18), with each curve associated with a value of the Autoregulation Index (ARI), ranging from ARI = 0 (absence of CA) to ARI = 9 (best observed CA). The best fit curve corresponded to the estimated value of ARI for the data (17). Values of ARI were only accepted if the coherence function was above its 95% confidence limit in the frequency interval 0.15 Hz to 0.25 Hz, and the normalized mean square error for fitting the Tiecks model was below 0.30 (19). Impaired dynamic CA was defined as ARI ≤ 4 (20). Baseline cerebral hemodynamic parameters are reported as the average over a 5-min baseline recording.
Additional collected data included age, gender, comorbidities, type of shock, Sequential Organ Failure Assessment (SOFA) score (on the day of measurements) (6), cardiac index (CI, VIGILEO Edwards Lifescience, Tokyo, Japan), lactate levels, arterial, and central venous blood gases (on the day of measurements), kidney function by Kidney Disease Improving Global Outcomes score, use of vasoactive drugs, and mechanical ventilation at the moment of TCD assessment and all these variables were collected for a different investigator as the TCD measurements.
Continuous variables were compared using the Student t test or the Mann–Whitney U test, and categorical variables were compared using Pearson chi-square test or Fisher exact test as appropriate, following the Shapiro-Wilk W statistic. Results are expressed as mean ± SD or medians with interquartile ranges. Linear regression and Pearson correlation coefficient were used to test for association between parameters. A P value < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 22.0 (SPSS, Chicago, Ill).
Forty-four patients with shock were recruited over the study period; TCD measurements were not satisfactory in 10 patients, four had no temporal acoustic window and five patients had acute neurological symptoms. A total of 25 patients with shock had completed studies; 28 healthy volunteers with good-quality recordings were included in the control group. Demographic and clinical characteristics of the study population are shown in Tables 1 and 2. The mean SOFA score was 10.8 ± 4.3. The most frequent forms of shock were septic (14 patients [56%]), distributive (nine patients [36%]) and cardiogenic (two patients [8%]). All patients received norepinephrine, while vasopressin was given to five (20%) and dobutamine to two (8%) patients. Data on blood test variables, lactate, blood gases, and concomitant therapies at the time of CA assessment are given in Table 2. Patients and controls had similar ages but different gender distributions.
None of the bilateral cerebral hemodynamic parameters showed significant differences between the right and left MCAs; therefore, values were averaged in further analyses (Table 3). Peripheral variables, BP and heart rate were different between groups (P = 0.001, P < 0.001; Table 3). Although, we did not find difference between mean CBFV (P = 0.527; Table 3), systolic CBFV and PI were higher in the shock group compared with the control group (P = 0.006; P = 0.001; Table 3).
The ARI was lower in shock patients (4.0 ± 2.0) compared with controls (5.9 ± 1.5; P = 0.001; Table 3 and Fig. 1). In the shock group, 11 patients (44.0%) had an ARI ≤ 4.0, suggestive of impaired CA, while in the control group there were only two volunteers with ARI≤4.0 (7.1%; P = 0.004) (Fig. 2).
A highly significant inverse relationship between the ARI and the SOFA score, collected on the day of measurement, was identified in the shock group (r = −0.63, P = 0.0008, Fig. 3). We did not find a significant association between the ARI and other variables, such as lactate, pH, PaCO2, haemoglobin, or temperature (Fig. S1 Supplementary material, Supplemental Digital Content, http://links.lww.com/SHK/B2). However, when dichotomizing the ARI values, we found higher lactate levels and SOFA score in the group of patients with ARI ≤ 4 (P = 0.017 and P = 0.002, respectively; Table 4).
In this study, we reported that the ARI, which is an effective tool to assess dynamic CA (18), was significantly lower in patients with circulatory shock when compared with healthy controls. Moreover, the percentage of patients showing impaired CA (ARI ≤ 4) was significantly higher than what was observed in controls. Of considerable relevance, the ARI showed a strong inverse relationship with the severity of organ dysfunction, as reflected by the SOFA score. Taken together, these findings suggest that impaired CA might be a common finding in circulatory shock thus warranting further investigation of the extent to which it could contribute to the occurrence of brain dysfunction in these patients.
Peripheral effects on cerebral hemodynamics
Better understanding of the pathophysiology of CBF regulation is of paramount importance for developing brain-protective strategies. The relevance of dynamic CA assessment is increasingly recognized in stroke, severe head injury, and other neurological conditions, but its value in non-neurological disease is seldom acknowledged (11, 21–23). Our findings add to previous work showing alterations in dynamic CA following cardiac surgery (24), hypertensive disorders of pregnancy (25), heart failure (16), and sepsis (26). The physiological mechanisms, whereby disturbances of the peripheral circulation affect cerebral hemodynamics, are puzzling and deserve further investigation. The strong inverse relationship between the ARI and SOFA, which we reported for the first time, points out toward specific organ-brain linkages. The SOFA score reflects a sequence of complications in the critically ill through dysfunction of organs like the liver, heart, kidney and lung, but also the brain, by incorporating a maximum of four points from the Glasgow Coma Score (6). Previous studies have reported dysfunction of the liver (27) and heart (16, 28), leading to worsening of CA, but our findings suggest that similar influences could be attributed to other organs as well. Due to our limited understanding of the cellular and subcellular mechanisms governing dynamic CA, the precise pathways whereby organ dysfunction affects dynamic CA are open to conjecture, but are likely to be multifactorial, as reflected by the SOFA score. In conditions like heart failure, where alterations in autonomic nervous system function are manifested, these could affect the neurogenic control of the cerebral circulation, although the extent and circumstances in which this form of control is operational is still open to debate (29, 30). In other conditions, such as sepsis, it is likely that the causal pathway will involve additional factors such as circulating hypoxia, disturbances in acid–base balance (26, 31, 32) or deactivation of the baroreceptor reflex (33, 34). From a mechanistic perspective, one would expect that the end result would be arteriolar smooth muscle contractility to be affected, thus leading to less efficient control of vessel diameter, leading to a decreased critical closure pressure due a loss of vascular resistance of the arterial bed caused by human endotoxemia (35). Even the correction of BP level by the use of vasopressors did not prevent this decrease in critical closing pressure promotes impairment of CA and contributes to cerebral dysfunction (36).
Our patients showed hyperlactatemia. Metabolic acidosis with lactate acidaemia and negative base excess is universally present in shock usually as a direct consequence of low perfusion and cellular hypoxia (37). Of interest, serum hyperlactatemia in neurosurgical patients without systemic complications has been associated with poor neurological outcomes and longer hospital stay (38). Although, we did not find a linear relationship between ARI and plasma lactate, the patients with low ARI (ARI ≤ 4) showed higher lactate when compared with patients with higher ARI (Table 4). This finding suggests that the deficit in oxygen delivery to the brain or impaired oxygen extraction is likely to play a role in depressing CA in shock patients (39). The signaling pathways modulated by acidosis have potential to fine tune vascular tone and adapt blood flow in response to physiological and pathophysiological changes in local metabolic demand. Recent evidence suggests that acute reductions in pH of vascular smooth muscle cells, possibly together with intracellular acidification of endothelial cells, counteract the vasorelaxation induced by acidosis. In this manner, sensing of the CO2/HCO3– buffer composition can initiate downstream responses that protect against edema, which could otherwise be the consequence of unopposed vasodilation (40).
These considerations, and the strong relationship we found between ARI and SOFA, raise the hypothesis that CA could be considered a marker of organ or peripheral circulatory dysfunction. More work is needed to improve our understanding of how peripheral disturbances, including organ dysfunction, affect the cerebral circulation. Experimental studies, inducing selective organ damage, could be particularly informative. Regarding other cerebral hemodynamic parameters, our results did not show a difference in CBFV mean between groups; however, we found a difference in systolic CBFV that led to increases in PI in the shock group. Changes in PI were first reported in 1986 (41). In 2004, Bellner et al. (41) concluded that PI can serve as a surrogate for estimating elevated intracranial pressure (42) or an increase of cerebrovascular resistance (42, 43). Furthermore, recent systematic review and meta-analysis reported that PI increases in early sepsis patients. However, an elevated PI has long been acknowledged to be a nonspecific finding, and the PI may be heavily influenced by the mean BP and PaCO2(43, 44), suggesting that the PI may be of limited use in clinical practice.
Brain dysfunction associated circulatory shock is cerebral dysfunction that accompanies shock in the absence of central nervous system infection and other possible causes of brain dysfunction (i.e., structural central nervous system lesions or drug overdose) (5, 7). In some types of shock, such as sepsis, brain dysfunction is probably the most frequent organ dysfunction, affecting up to 70% of patients with sepsis and frequently occurring early, often before any other organ involvement (45). The pathophysiology of this condition is still unclear and probably multifactorial, involving diffuse neuroinflammation, excitotoxicity, and micro cerebral ischaemia (46). Our results demonstrated that CA impairment is also present in 44% of patients with shock and from this it is possible to speculate that disturbances in CBF regulation may play a key role in the development of brain dysfunction.
Treatment of hypotension in shock follows the principle that maintaining mean BP above the lower limit of CBF autoregulation, thought to be between 50 mm Hg and 60 mm Hg, should ensure cerebral perfusion (7, 47). However, this approach would be ineffectual if CA is impaired or depressed in shock patients, such as we demonstrated in our study. Moreover, a standard universal target for minimum BP would not consider individual patients’ requirements. The availability of methods to monitor CA provides the opportunity to test the variability and importance of individualized hemodynamic goals on outcomes, and, in the future, it may provide the opportunity to individualize BP targets during shock (48, 49).
TCD has been instrumental in studies of cerebral dysfunction in different types of shock (32, 50). Pratt et al. showed that the CBFV and resistance index changed after 60 min of haemorrhagic shock (50). In addition, Terborg et al. (36) concluded that there was vasoparalysis in septic shock following reductions in cerebrovascular reactivity. However, contrary to our findings, they reported that the CA was intact in these patients (36). On the other hand, Crippa et al. (26) recently showed that CA was altered in half of the patients with sepsis and was an independent predictor of brain dysfunction associated with sepsis. Following the new international consensus of sepsis (SEPSIS 3.0) (51), we acknowledge that sepsis formed an important sub-group in our sample (n = 14/25). The identification of cerebral hemodynamic parameters that could pinpoint the high-risk sub-groups for brain damage in shock patients would be worth pursuing in future investigations.
Therefore, patient‘s autoregulatory status might be an important monitoring issue. The idea of treating patients with an “optimal cerebral autoregulation”(TBI or SAH) or “optimal BP” regime is not firmly established; our results could make the link between CA status and possible treatments. However, these methods still await prospective clinical trials (52) to evaluate outcomes and establish the prognostic value of CA in these patients. Bedside CA evaluation may allow for adequate therapeutic measures to be taken using our method for noninvasive assessment of cerebral circulatory status in patients experiencing shock. In addition, impairment of CA as a marker of cerebral dysfunction should be investigated.
Our study has limitations. Although patient inclusion followed strict criteria, different types of shock were included and differences in physiopathology may have influenced our results. Despite the relatively small number of patients, the highly significant differences we detected demonstrate that the sample size was adequate. In particular, for the ARI we detected a difference of 1.9 units, with n = 25 patients, whilst the study by Brodie et al. (53) indicated that n = 11 subjects would suffice to detect a difference in ARI = 2. To the best of our knowledge this is the first study to report the dynamic CA in patients with shock and hopefully it will be followed by much larger studies to confirm its findings. Of particular relevance, more homogenous patient groups would be desirable, to improve our understanding of the role of pathophysiology on CA impairment, for example in haemorrhagic shock that was not represented in our patient group. Second, for logistic reasons we have not been able to perform measurements of EtCO2 in controls, but several studies have shown that EtCO2 is not significantly altered in healthy subjects at rest (20). The lack of matching for sex is also a limitation of the study, however the large majority of studies have not detected any effects of sex on cerebral haemodynamics (20, 54, 55). Finally, this study was purely observational. Future work is needed to pave the way for interventional studies to assess the value of CA-based protocols for management of patients in shock. Variables that could be managed such as BP, temperature and PaCO2, that were previously reported to affect CA, should be tested as part of trials investigating whether personalized, tight control of these variables could reduce the incidence of organ dysfunction in patients with shock.
The present study demonstrated that circulatory shock is often associated with impaired CA. Furthermore, in patients with shock, there was strong association between the severity of CA alterations and multiple organ failure, reinforcing the need to monitor cerebral hemodynamics in this setting. Further work is needed to elucidate the underlying mechanisms of impaired dynamic CA in patients with shock and to assess different strategies to minimize the effects of impaired CA in these patients.
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