Transcranial doppler assessment of cerebral perfusion in critically ill septic patients: a pilot study
© Pierrakos et al.; licensee Springer. 2013
Received: 14 March 2013
Accepted: 8 August 2013
Published: 22 August 2013
The aim of this study is to evaluate the feasibility and efficacy of Transcranial Doppler (TCD) in assessing cerebral perfusion changes in septic patients.
Using TCD, we measured the mean velocity in the middle cerebral artery (VmMCA, cm/sec) and calculated the pulsatility index (PI), resistance index (RI) and cerebral blood flow index (CBFi = 10*MAP/1.47PI) on the first day of patients’ admission or on the first day of sepsis development; measurements were repeated on the second day. Sepsis was defined according to standard criteria.
Forty-one patients without any known neurologic deficit treated in our 24-bed Critical Care Unit were assessed (Sepsis Group = 20, Control Group = 21). Examination was feasible in 91% of septic and 85% of non-septic patients (p = 0.89). No difference was found between the two groups in mean age, mean arterial pressure (MAP) or APACHE II score. The pCO2 values were higher in septic patients (46 ± 12 vs. 39 ± 4 mmHg p < 0.01). No statistically significant higher values of VmMCA were found in septic patients (110 ± 34 cm/sec vs. 99 ± 28 cm/sec p = 0.17). Higher values of PI and RI were found in septic patients (1.15 ± 0.25 vs. 0.98 ± 0.16 p < 0.01, 0.64 ± 0.08 vs. 0.59 ± 0.06 p < 0.01, respectively). No statistically significant lower values of CBFi were found in septic patients (497 ± 116 vs. 548 ± 110 p = 0.06).
Our results suggest cerebral vasoconstriction in septic compared to non-septic patients. TCD is an efficient and feasible exam to evaluate changes in cerebral perfusion during sepsis.
KeywordsEncephalopathy Sepsis Cerebral vasoconstriction Cerebral microcirculation Pulsatility index Resistance index
Sepsis-associated encephalopathy (SAE) may develop in more than 50% of septic patients[1, 2]. It is one of the most common causes of delirium in intensive care units, where it is an independent prognostic factor for increased mortality. Additionally, it is suspected of contributing to long-term cognitive impairment.
The pathogenesis of SAE remains unclear. Alterations in cerebral perfusion during sepsis possibly play an important role in the development of this clinical entity. Microcirculatory dysfunction and dissociation between cerebral cells’ needs and perfusion at several cerebral areas was found in an experimental sepsis model[7, 8]. However, in humans, microcirculatory dysfunction is not widely assessed, as, to date, no widely applicable method exists to evaluate cerebral perfusion. Existing attempts to evaluate cerebral blood flow and microcirculation in humans during sepsis are limited to a small number of selected patients[10, 11]. Transcranial Doppler (TCD) is a readily available and reproducible technique by which cerebral perfusion can be evaluated in everyday clinical practice. Indirect cerebral microcirculation assessment by testing cerebral autoregulation in response to several stimulations with TCD has been previously performed[12–17]. However, these methods are relatively complicated and not easily applicable. The aim of this study is to assess static cerebral perfusion characteristics and changes in septic versus non-septic critically ill patients.
This is a prospective observational study that was conducted in our 24-bed intensive care unit during a three-month period (July 2011 to September 2011). The study group consisted of 20 consecutive patients who developed sepsis in a period of 48 hours after their admission (sepsis group). Sepsis was defined according to standard international criteria. We also enrolled 21 patients without any signs of infection on their ICU admission who were expected to stay in the ICU for more than 24 h (Control Group). The Ethics Committee of Mont-Godinne University Hospital approved the study protocol and verbal consent was obtained from all patients or from relatives in cases where the patient was not conscious.
Exclusion criteria for both groups were as follows: 1) age < 18 years old, 2) known cerebral lesion (ischemic or haemorrhagic cerebrovascular event, neoplasm), 3) cerebral infection, 4) encephalopathy associated with hyperuremia, hypernatremia or hypoglycaemia, 5) hepatic encephalopathy, 6) patient supported by Intra-Aortic Balloon Pump or by ECMO, 7) non-sinusal rhythm, 8) known severe carotid stenosis (>70%), or 9) history of extended cervical operation.
Demographic data on all patients and diagnosis on ICU admission were recorded. The source of sepsis, relevant microbiological results, and treatments, including administration of adrenergic and sedative agents, were recorded. The neurology status was evaluated from GCS. For the septic patients who were intubated or nonseptic patients who were intubated urgently, the GCS before the administration of sedatives was registered. For the nonseptic patients who were intubated electively, the GCS was evaluated 6 h after the sedation cessation. For the rest of the patients, the GCS on the first day of inclusion in the study was recorded. The severity of critical illness was assessed from the Acute Physiology and Chronic Health Evaluation (APACHE) II score.
Mean velocity in the middle cerebral artery (VmMCA) was measured using a 2-MHz TCD probe through the temporal bone window on both sides of the skull, twice within the first 48 h after the confirmation of sepsis diagnosis for the septic group or after ICU admission for patients in the control group. An interval period of more than 20 h between the two measurements was ensured. Each measurement on each side of the brain was repeated three times and the highest value was considered for our analysis. The average of the two values on the two brain sides was registered. A difference in depth of 0.5 cm between the two sides was considered acceptable. At the time of the measurements, the patients were in a stable hemodynamic status. Pulsatility index (PI) (PI = Velocity systolic-Velocity diastolic/mean velocity) and Cerebrovascular resistant index (RI) (RI = Velocity Systolic–Velocity diastolic/Velocity Systolic) were calculated. Previous experimental data showed a strong inverse correlation between PI and the logarithm of regional cerebral blood flow measured by laser Doppler (r2 = 0.81). From the formula that was provided (logCBF = 1.11-0.17*PI), we found that the antilogarithm of CBF was related to the PI with the following formula CBF = 10/1.47PI. Based on this formula, and given that cerebral blood flow (CBF) is estimated by the formula Perfusion Pressure/cerebrovascular resistances, we considered PI relate to cerebral resistances (CBVR) accordingly: CBVR ≈ 1.47PI/10. We evaluated the ratio MAPx10/1.47PI as an index of CBF.
The primary endpoint of the study was the identification of any differences in the values of VmMCA and/or PI and/or RI in septic patients compared to non-septic critically ill patients.
Statistical analysis was performed with SPSS software (SPSS Inc., Chicago, IL). A Kolomogorov-Smirnov test was used to verify the normality of distribution of continuous variables. Student’s t test was used for continuous variables. Categorical variables were compared by Fisher’s exact test. Pearson’s correlation was applied to evaluate the relationships between VMCA, PI, RI, and pCO2 or MAP and between VMCA and CBFi. Statistical significance was defined as p < 0.05.
Demographic and hemodynamic characteristics of the patients
67 ± 14
67 ± 11
Type of patients
21 ± 7
20 ± 5
GCS < 14f
9 ± 5
14 ± 1
77 ± 14
79 ± 19
9.4 ± 1.4
10.1 ± 1.4
46 ± 12
39 ± 4
7.39 ± 0.09
7.37 ± 0.05
Pulmonary infection was the source of infection in the majority of septic patients (60%). Gram-negative pathogens were responsible for sepsis in 50% of septic patients. Twelve (66%) septic patients presented with one or more organ dysfunctions and (61%) had deterioration in their level of consciousness (GCS < 14).
Pooled data (days 1 and 2) of Transcranial Doppler measurements for the two groups of patients
VMCA systolic (cm/sec)
192 ± 59
166 ± 51
VMCA diastolic (cm/sec)
68 ± 26
67 ± 18
VMCA mean (cm/sec)
110 ± 34
99 ± 28
Pulsatility Index (PI)
1.15 ± 0.25
0.98 ± 0.16
Resistance index (RI)
0.64 ± 0.08
0.59 ± 0.06
497 ± 116
548 ± 110
Day 1 data of Transcranial Doppler measurements for the two groups of patients
VMCA systolic (cm/sec)
189 ± 13
153 ± 12
VMCA diastolic (cm/sec)
67 ± 6
61 ± 3
VMCA mean (cm/sec)
106 ± 7
91 ± 5
Pulsatility Index (PI)
1.15 ± 0.06
0.99 ± 0.04
Resistance index (RI)
0.64 ± 0.02
0.60 ± 0.01
469 ± 115
521 ± 113
Day 2 data of Transcranial Doppler measurements for the two groups of patients
VMCA systolic (cm/sec)
195 ± 15
179 ± 12
VMCA diastolic (cm/sec)
68 ± 6
74 ± 5
VMCA mean (cm/sec)
112 ± 8
108 ± 7
Pulsatility Index (PI)
1.16 ± 0.06
0.96 ± 0.03
Resistance index (RI)
0.65 ± 0.01
0.58 ± 0.01
498 ± 120
576 ± 104
Correlations of mean velocity in middle cerebral artery (VmMCA), pulsatility index (PI), resistance index (RI) and mean arterial pressure (MAP), pCO 2
The most important finding of this study is that TCD can be used in the evaluation of cerebral perfusion in septic patients. It is a noninvasive and feasible exam, because only two septic patients were not suitable for assessment as a result of an unsatisfactory echographic window. PI and RI were found to be increased in the sepsis group, suggesting early changes in cerebral perfusion during sepsis, as all of our patients were in sepsis for less than 48 hours.
Previous TCD studies performed in septic patients have focused on cerebral vasoreactivity in response to acetazolamide administration[12, 13] or carbon dioxide[14, 15] and blood pressure modifications, with conflicting results. In contrast, static measurements of VmMCA were performed in our study with the calculation of PI as well as RI, and gross estimation of cerebral blood flow was made.
RI and PI are two parameters that are commonly used to describe the Doppler wave. In vitro and in vivo studies show that both indexes are related to changes in peripheral vascular resistances[23–25]. Increased PI is associated with angiographically demonstrated diffuse intracranial vessel disease, and both RI and PI have been found to be increased in patients who suffer from diabetes with microangiopathy or advanced cirrhosis with encephalopathy[27, 28]. The increased values of PI and RI that we observed in septic patients (compared with control critically ill patients) should be interpreted as a manifestation of enhanced vascular resistance in the cerebral circulation during early sepsis. This observation is consistent with previous experimental data documenting impaired cerebral microcirculation at the onset of septic shock as well as in septic patients with delirium, where PI was found to be increased compared with healthy controls. In this study, in contrast, we compared septic patients to a control group of critically ill patients to exclude critical illness-related factors (possibly including sedation, nonseptic inflammatory reaction, operation stress or catecholamines administration) that could affect cerebrovascular resistances. Patients from the control group had a similar PI to healthy people of the same age (0.98 ±16 vs. 0.95 ± 17 or 0.97[0.93-1.02]). Interestingly, on the first day, when microcirculation changes are expected to be less severe[29, 32], only PI and not RI was found to be statistically higher in septic patients compared with the controls. This may be explained by the fact that PI seems to have greater sensitivity to reflect changes in cerebrovascular resistances than RI[33, 34]. On the other hand, the results of our study support the hypothesis that changes in cerebral microcirculation start early in sepsis, whereas they are more well identified several hours after sepsis onset (>24 h) (Tables 3 and4).
In our study, septic patients had higher arterial pCO2 than control patients. Acute hypercapnia normally causes intense cerebral vasodilation if vascular autoregulation is preserved. It therefore seems unlikely that higher pCO2 could account for the changes in vascular resistances that we observed in our septic patients, because any modifications would have been expected to be in the opposite direction. Cerebral autoregulation, however, has been shown to be influenced by carbon dioxide levels in patients with septic shock, with more profound alterations in autoregulation detected in hypercapnic (pCO2 > 40 mmHg) than hypocapnic (pCO2 < 40 mmHg) patients. The relative vasodilation that was expected in our septic group (due to higher PaCO2) may thus have been partly blunted in some patients due to severe sepsis; however, this effect, if present, was only marginal, because we did not find any correlation between the levels of pCO2 and PI or RI (Table 5).
Our study entails several limitations. First, the study was not blinded and the number of patients was relatively small; our results should thus be confirmed in a larger study with an ultrasonographer blinded for the presence of sepsis. A second theoretical limitation of our study relates to the possible operator-dependency and subjectivity of the ultrasound measurements. It is well established, however, that PI and RI measurements do not depend on the insonation angle applied by the performer. Also, we did not repeat the TCD studies beyond the two consecutive study days; therefore, we do not know whether the observed TCD abnormalities were transient or persisted throughout the sepsis period. Finally, as far as SAE is concerned, the relatively small number of our study patients precludes any attempt to correlate neurological symptoms with TCD measurements or derived parameters. However, the higher number of septic patients with abnormal GCS (GCS < 14) may suggest a relation between our findings and clinical signs of SAE.
Our results suggest that cerebral vascular constriction is detectable by TCD in the early stage of sepsis. TCD can be a useful tool to evaluate cerebral vascular tone and possibly cerebral perfusion in critically ill septic patients. Further studies are warranted to confirm the increases in PI and RI in sepsis patients and to assess the clinical significance of these results.
- Papadopoulos MC, Davies DC, Moss RF, Tighe D, Bennett ED: Pathophysiology of septic encephalopathy: a review. Crit Care Med 2000,28(8):3019–3024. 10.1097/00003246-200008000-00057View ArticlePubMedGoogle Scholar
- Wilson JX, Young GB: Progress in clinical neurosciences: sepsis-associated encephalopathy: evolving concepts. Can J Neurol Sci 2003,30(2):98–105.PubMedGoogle Scholar
- Bleck TP, Smith MC, Pierre-Louis SJ, Jares JJ, Murray J, Hansen CA: Neurologic complications of critical medical illnesses. Crit Care Med 1993,21(1):98–103. 10.1097/00003246-199301000-00019View ArticlePubMedGoogle Scholar
- Eidelman LA, Putterman D, Putterman C, Sprung CL: The spectrum of septic encephalopathy. Definitions, aetiologies, and mortalities. JAMA 1996,275(6):470–473. 10.1001/jama.1996.03530300054040View ArticlePubMedGoogle Scholar
- Barichello T, Martins MR, Reinke A, Feier G, Ritter C, Quevedo J, Dal-Pizzol F: Long-term cognitive impairment in sepsis survivors. Crit Care Med 2005,33(7):1671. 10.1097/01.CCM.0000170192.54682.C1View ArticlePubMedGoogle Scholar
- Burkhart CS, Siegemund M, Steiner LA: Cerebral perfusion in sepsis. Crit Care 2010,14(2):215. 10.1186/cc8856PubMed CentralView ArticlePubMedGoogle Scholar
- Rosengarten B, Wolff S, Klatt S, Schermuly RT: Effects of inducible nitric oxide synthase inhibition or norepinephrine on the neurovascular coupling in an endotoxic rat shock model. Crit Care 2009,13(4):R139. 10.1186/cc8020PubMed CentralView ArticlePubMedGoogle Scholar
- Mihaylova S, Killian A, Mayer K, Pullamsetti SS, Schermuly R, Rosengarten B: Effects of anti-inflammatory vagus nerve stimulation on the cerebral microcirculation in endotoxinemic rats. J Neuroinflammation 2012, 9: 183. 10.1186/1742-2094-9-183PubMed CentralView ArticlePubMedGoogle Scholar
- Sharshar T, Polito A, Checinski A, Stevens RD: Septic-associated encephalopathy–everything starts at a microlevel. Crit Care 2010,14(5):199. 10.1186/cc9254PubMed CentralView ArticlePubMedGoogle Scholar
- Bowton DL, Bertels NH, Prough DS, Stump DA: Cerebral blood flow is reduced in patients with sepsis syndrome. Crit Care Med 1989,17(5):399–403. 10.1097/00003246-198905000-00004View ArticlePubMedGoogle Scholar
- Sharshar T, Carlier R, Bernard F, Guidoux C, Brouland JP, Nardi O, De la Grandmaison GL, Aboab J, Gray F, Menon D, Annane D: Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med 2007,33(5):798–806. 10.1007/s00134-007-0598-yView ArticlePubMedGoogle Scholar
- Fülesdi B, Szatmári S, Antek C, Fülep Z, Sárkány P, Csiba L, Molnár C: Cerebral vasoreactivity to acetazolamide is not impaired in patients with severe sepsis. J Crit Care 2012,27(4):337–343. 10.1016/j.jcrc.2011.11.002View ArticlePubMedGoogle Scholar
- Szatmári S, Végh T, Csomós A, Hallay J, Takács I, Molnár C, Fülesdi B: Impaired cerebrovascular reactivity in sepsis-associated encephalopathy studied by acetazolamide test. Crit Care 2010,14(2):R50. 10.1186/cc8939PubMed CentralView ArticlePubMedGoogle Scholar
- Bowie RA, O’Connor PJ, Mahajan RP: Cerebrovascular reactivity to carbon dioxide in sepsis syndrome. Anaesthesia 2003,58(3):261–265. 10.1046/j.1365-2044.2003.29671.xView ArticlePubMedGoogle Scholar
- Matta BF, Stow PJ: Sepsis-induced vasoparalysis does not involve the cerebral vasculature: indirect evidence from autoregulation and carbon dioxide reactivity studies. Br J Anaesth 1996,76(6):790–794. 10.1093/bja/76.6.790View ArticlePubMedGoogle Scholar
- Taccone FS, Castanares-Zapatero D, Peres-Bota D, Vincent JL, Berre’ J, Melot C: Cerebral autoregulation is influenced by carbon dioxide levels in patients with septic shock. Neurocrit Care 2010,12(1):35–42. 10.1007/s12028-009-9289-6View ArticlePubMedGoogle Scholar
- Rosengarten B, Krekel D, Kuhnert S, Schulz R: Early neurovascular uncoupling in the brain during community acquired pneumonia. Crit Care 2012,16(2):R64. 10.1186/cc11310PubMed CentralView ArticlePubMedGoogle Scholar
- Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: International sepsis definitions conference. 2001SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Intensive Care Med 2003,29(4):530–538. 10.1007/s00134-003-1662-xView ArticlePubMedGoogle Scholar
- Gosling RG, King DH: Arterial assessment by Doppler-shift ultrasound. Proc R Soc Med 1974,67(6 Pt 1):447–449.PubMed CentralPubMedGoogle Scholar
- Tranquart F, Berson M, Bodard S, Roncin A, Pourcelot L: Evaluation of cerebral blood flow in rabbits with transcranial Doppler sonography: first results. Ultrasound Med Biol 1991,17(8):815–818. 10.1016/0301-5629(91)90164-RView ArticlePubMedGoogle Scholar
- Nagai H, Moritake K, Takaya M: Correlation between transcranial Doppler ultrasonography and regional cerebral blood flow in experimental intracranial hypertension. Stroke 1997,28(3):603–607. 10.1161/01.STR.28.3.603View ArticlePubMedGoogle Scholar
- Taylor KJ, Holland S: Doppler US. Part I. Basic principles, instrumentation, and pitfalls. Radiology 1990,174(2):297–307.View ArticlePubMedGoogle Scholar
- Spencer JA, Giussani DA, Moore PJ, Hanson MA: In vitro validation of Doppler indices using blood and water. J Ultrasound Med 1991,10(6):305–308.PubMedGoogle Scholar
- Legarth J, Nolsoe C: Doppler blood velocity waveforms and the relation to peripheral resistance in the brachial artery. J Ultrasound Med 1990,9(8):449–453.PubMedGoogle Scholar
- Halpern EJ, Merton DA, Forsberg F: Effect of distal resistance on Doppler US flow patterns. Radiology 1998,206(3):761–766.View ArticlePubMedGoogle Scholar
- Sharma VK, Tsivgoulis G, Lao AY, Malkoff MD, Alexandrov AV: Noninvasive detection of diffuse intracranial disease. Stroke 2007,38(12):3175–3181. 10.1161/STROKEAHA.107.490755View ArticlePubMedGoogle Scholar
- Kawakami M, Koda M, Murawaki Y, Kawasaki H, Ikawa S: Cerebral vascular resistance assessed by transcranial color Doppler ultrasonography in patients with chronic liver diseases. J Gastroenterol Hepatol 2001,16(8):890–897. 10.1046/j.1440-1746.2001.02479.xView ArticlePubMedGoogle Scholar
- Lee KY, Sohn YH, Baik JS, Kim GW, Kim JS: Arterial pulsatility as an index of cerebral microangiopathy in diabetes. Stroke 2000,31(5):1111–1115. 10.1161/01.STR.31.5.1111View ArticlePubMedGoogle Scholar
- Taccone FS, Su F, Pierrakos C, He X, James S, Dewitte O, Vincent JL, De Backer D: Cerebral microcirculation is impaired during sepsis: an experimental study. Crit Care 2010,14(4):R140. 10.1186/cc9205PubMed CentralView ArticlePubMedGoogle Scholar
- Tegeler CH, Crutchfield K, Katsnelson M, Kim J, Tang R, Passmore Griffin L, Rundek T, Evans G: Transcranial Doppler velocities in a large, healthy population. J Neuroimaging 2012,23(3):466–472.View ArticlePubMedGoogle Scholar
- Martin PJ, Evans DH, Naylor AR: Transcranial color-coded sonography of the basal cerebral circulation. Reference data from 115 volunteers. Stroke 1994,25(2):390–396. 10.1161/01.STR.25.2.390View ArticlePubMedGoogle Scholar
- Sitina M, Turek Z, Parizkova R, Lehmann C, Cerny V: Preserved cerebral microcirculation in early stages of endotoxemia in mechanically-ventilated rabbits. Clin Hemorheol Microcirc 2011,47(1):37–44. 10.3233/CH-2010-1363PubMedGoogle Scholar
- Greisen G: Analysis of cerebroarterial Doppler flow velocity waveforms in newborn infants: towards an index of cerebrovascular resistance. J Perinat Med 1986,14(3):181–187. 10.1515/jpme.1922.214.171.124View ArticlePubMedGoogle Scholar
- Grubb BP, Gerard G, Roush K, Temesy-Armos P, Montford P, Elliott L, Hahn H, Brewster P: Cerebral vasoconstriction during head-upright tilt-induced vasovagalsyncope. A paradoxic and unexpected response. Circulation 1991,84(3):1157–1164. 10.1161/01.CIR.84.3.1157View ArticlePubMedGoogle Scholar
- Vajda Z, Büki A, Vetö F, Horváth Z, Sándor J, Dóczi T: Transcranial Doppler-determined pulsatility index in the evaluation of endoscopic third ventriculostomy (preliminary data). Acta Neurochir (Wien). 1999,141(3):247–250. 10.1007/s007010050294View ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.