Intensive Care Med (2000) 26: 202±205 Ó Springer-Verlag 2000
L. Mascia P. J. D. Andrews E. G. McKeating M. J. Souter M. V. Merrick I. R. Piper
Received: 28 May 1999 Final revision received: 20 September 1999 Accepted: 5 November 1999 This work was supported by the Medical Research Council, Special Project Grant, G9508752
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L. Mascia ( ) Istituto di Anestesiologia e Rianimazione, Ospedale Policlinico, Università di Bari, Piazza G Cesare 11, 70 122 Bari, Italy e-mail:
[email protected] Tel.: + 39-0 80-5 47 87 94 Fax: 39-0 80-5 47 87 94) P. J.D. Andrews ´ E. G. McKeating ´ M. J. Souter Department of Anaesthetics, Western General Hospital, University of Edinburgh, UK M. V. Merrick Department of Nuclear Medicine, Western General Hospital, University of Edinburgh, UK I. R. Piper Department of Clinical Physics, Institute of Neurological Sciences, Glasgow, UK
B R I E F RE PO RT
Cerebral blood flow and metabolism in severe brain injury: the role of pressure autoregulation during cerebral perfusion pressure management
Abstract Objective: To ascertain if norepinephrine can be used as part of the cerebral perfusion pressure (CPP) management to increase arterial blood pressure (MAP) without causing cerebral hyperemia after severe head injury (HI). Design: Prospective, interventional study. Setting: Intensive care unit in a university hospital. Patients: Twelve severely HI patients; median Glasgow Coma Scale was 6 (range 3±8). Interventions: CPP management ( = 70 mmHg). Pressure autoregulation (assessed by norepinephrine infusion) was defined intact if %CPP/ %CVR £ 2. Results: Cerebral blood flow (CBF: Xe133 inhalation technique), jugular bulb oxygen saturation (SjO2) and transcranial Doppler (TCD) were recorded during the test. Norepinephrine increased CPP by 33 % ( 4). Autoregulation was found to be intact in ten patients and defective in two. In the ten patients with preserved autoregulation, CBF de-
Introduction Vascular engorgement and edema formation have been proposed as two mechanisms responsible for raised intracranial pressure (ICP) after severe head injury (HI). Vascular mechanisms have been advocated as the basis for cerebral perfusion pressure (CPP) management described by Rosner et al. [1]. If cerebral blood flow
creased from 31 3 to 28 3 ml/ 100 g/min; in the two patients with impaired autoregulation CBF increased respectively from 16 to 35 and from 21 to 70 ml/100 g/min. SjO2 did not change significantly from baseline. TCD remained within the normal range. Conclusions: During CPP management norepinephrine can be used to increase MAP without potentiating hyperemia if pressure autoregulation is preserved. The assessment of pressure autoregulation should be considered as a guide for arterial pressure-oriented therapy after HI. Key words Cerebral blood flow ´ CPP management ´ Intracranial pressure ´ Pressure autoregulation
(CBF) autoregulation is intact, periods of intracranial hypertension may be avoided by keeping CPP above the threshold value of 70 mmHg. However, the risk of hyperemia may limit such an approach. The disruption of the blood-brain barrier (BBB) leading to the formation of vasogenic edema is the basis of the ªLund therapyº [2]. This approach suggests reduction of capillary pressure by a mild reduction in
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blood pressure while colloid osmotic pressure is increased with albumin. If autoregulation is impaired, even if CPP remains constant, but both BP and ICP fall, there will be reduction in CBF. Conversely, if autoregulation is preserved, a fall in BP will induce an increase in ICP leading to a further reduction in CPP. Therefore the assessment of pressure autoregulation may be a key factor to guide therapy. We hypothesized that norepinephrine could be used to increase arterial blood pressure without potentiating cerebral hyperemia. To address this hypothesis pressure autoregulation was assessed in severe HI patients treated with CPP management.
Methods This research project was approved by the Ethics committee and written informed consent was given by the patient's next of kin. Twelve severe HI patients admitted consecutively to the intensive care unit (ICU), University of Edinburgh, were studied (see Table 1). The median Glasgow Coma Scale score on admission was 6 (range 3±8). The intracranial pathology was defined as focal or diffuse. Routine monitoring involved ECG, pulse oximetry, body temperature, arterial pressure, central venous pressure, ICP, arterial, jugular [3] oxyhemoglobin saturation and blood gases. CPP was calculated as the arithmetic difference between MAP and mean ICP with reference to the external auditory meatus. Patients were ventilated to maintain arterial PO2 > 13 kPa and arterial PCO2 of approximately 4.5 kPa. The protocol for CPP management proposed by Rosner et al. [1] was applied; the threshold value for active CPP treatment was 70 mmHg. Any hematoma causing significant midline shift, detected on the admission CT scan was surgically evacuated. Regional CBF was obtained using the Xe133 inhalation technique [4] before and during norepinephrine infusion. CBF was calculated as the initial slope index (Cerebrograph, Novo 10 a, Novodiagnostic, Denmark). Transcranial Doppler (TCD) insonation (EME TC2±64 B Überlingen, Germany) of the middle cerebral artery (MCA) was performed as previously described [5]. Pressure autoregulation was tested by norepinephrine infusion (0.006±0.1 mg/kg/min) to raise MAP by 30 % and defined intact if %CPP/%CVR £ 2 [3]. SjO2 and TCD were continuously recorded during the test. CBF was normalized to a value at PaCO2 of 34 mmHg [3]. CBF(34) was defined according to Obrist et al. [4]. An SjO2 ³ 76 % and £ 50 % was considered respectively as index of hyperemia or increased cerebral extraction of oxygen [3]. An MCA mean flow velocity (MFV) greater than 100 cm/s was considered abnormally high [5]. Statistical analyses were by ANOVA test; data are expressed as mean SEM.
Results Twelve tests were performed within 2 days from admission. Autoregulation was found to be intact in ten patients and defective in two. Norepinephrine infusion increased MAP by 26 % ( 3) and reduced ICP by 15 % ( 6), leading to an increase in CPP of 33 % ( 4). In
the two patients with impaired autoregulation ICP remained stable in one and decreased in the other. In the ten patients with preserved autoregulation, the mean CBF decreased from 31 3 to 28 3 ml/ 100 g/min. In the two with impaired autoregulation CBF increased respectively from 16 to 35 and from 21 to 70 ml/100 g/min (Fig. 1). In the total sample SjO2 increased from 67 % ( 3) to 73 % ( 3). Of the ten patients with preserved autoregulation, six had reduced CBF and four ªrelativeº hyperemic blood flow at baseline and did not change significantly from baseline (p = 0.2; Fig. 1). The mean CBF was statistically different between the two groups with reduced CBF and relative hyperemia both at baseline and during the test (p < 0.001). In four of six patients with reduced CBF, SjO2 was within the normal range at baseline and remained stable during the test (Fig. 1). The remaining two patients with reduced CBF had SjO2 in the hyperemic range (Fig. 1). In two of the four patients with ªrelativeº hyperemic CBF, SjO2 confirmed hyperemia (Fig. 1). There was no difference in SjO2 between the two groups with reduced CBF and relative hyperemia (p = 0.4). In the two patients with impaired autoregulation SjO2 increased during the test respectively from 66 % to 75 % and from 64 % to 73 % (Fig. 1). The MFV of the MCA increased from 59 ( 4) to 63 ( 4) cm/s. In the two patients with impaired autoregulation, TCD increased respectively from 80 to 90 and from 59 to 64 cm/s (Fig. 1). There was no difference in TCD between the two groups with reduced CBF and relative hyperemia (p = 0.3). PaCO2 remained stable during the study.
Discussion Our data suggest that norepinephrine can be used as part of the CPP management to increase blood pressure without potentiating cerebral hyperemia only if pressure autoregulation is preserved. Vascular engorgement and edema (vasogenic and/or cytotoxic) are two mechanisms responsible for raised ICP. Rosner et al. [1] suggested that if autoregulation is intact, the lowest ICP should occur when CPP is in the midrange of autoregulation (90±100 mmHg), because cerebral blood volume is minimal when vasoconstriction is maximal. A direct dependency of ICP on MAP is expected when CPP is below the lower limit of autoregulation and/or if autoregulation is impaired. According to this approach, CPP may be iatrogenically elevated inducing systemic hypertension if two conditions are fulfilled: (1) pressure autoregulation is preserved; (2) CPP is manipulated within the autoregulation range (60±160 mmHg). Systemic hypertension has been considered harmful if autoregulation is impaired. This concern arises princi-
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Fig. 1 CPP, CBF, SjO2 and TCD individual data during pressure autoregulation test (BL baseline, NI norepinephrine infusion). Dotted lines patients with impaired autoregulation (n = 2), continuous lines with open circles patients with reduced CBF (n = 6), continuous lines with closed circles patients with ªrelativeº hyperemic CBF (n = 4). The limits for reduced CBF ( < 32.9 ml/100 g/ min), ªrelativeº hyperemic CBF (32.9±55.3 ml/100 g/min), increased oxygen extraction (SjO2 < 50 %) and hyperemia (SjO2 > 76 %) are defined by two horizontal lines
Table 1 Demographic data and baseline values of the patient population Patient
Age (sex)
CT scan
Basal MAP (mm Hg)
Basal ICP (mm Hg)
1 2 3 4 5 6 7 8 9 10 11 12
63 (M) 22 (F) 15 (M) 60 (F) 19 (M) 25 (M) 32 (M) 33 (F) 20 (M) 19 (M) 38 (M) 21 (M)
Focal Diffuse Focal Focal Diffuse Diffuse Diffuse Diffuse Diffuse Diffuse Diffuse Diffuse
95 80 80 85 65 75 95 95 90 85 110 95
10 15 13 12 13 7 10 12 10 6 37 13
pally from two studies. Langfitt et al.[6], in a model of raised ICP, showed that vasomotor paralysis was the mechanism responsible for the increase in brain volume and ICP. This occurred in a late stage of ªprogressive decompensationº due to an increase in ICP equal to 90 mmHg with a reduction in CPP close to 20 mmHg. At that point the infusion of norepinephrine induced an increase in MAP followed by a progressive and consistent rise in ICP. Marshall et al. [7] reported that in a model of head injury pressure autoregulation was impaired: to test autoregulation MAP was increased to values higher than 160 (upper limit for autoregulation). The ªLund therapyº [2], is based on the concept that after HI the BBB is opened and that brain edema is the predominant cause of raised ICP. Since the employment
of mild reduction in blood pressure and induced cerebral vasoconstriction is effective in reducing ICP, this implies a direct dependency of ICP from MAP. Asgeirsson et al. [2] manipulated MAP obtaining CPP < 60 mmHg. A direct dependency of the ICP from MAP was therefore expected, either because CPP was below the lower limit of autoregulation or because autoregulation was impaired. In our study, during the test, mean CPP increased from 75 mmHg ( 3) to 100 mmHg ( 3); therefore, we shifted CPP toward the midrange (90±100 mmHg), where the lowest ICP was expected to occur. Consequently mean ICP decreased from 13 mmHg ( 2) to 11 mmHg ( 2). In the two patients with impaired autoregulation ICP did not increase during the test; the absolute values of ICP (15 and 10 mmHg respectively) were normal and therefore probably the buffering capacity of the craniospinal system was not exhausted. Moreover, cerebral and hemodynamic stability was required to perform the test; this can explain why most of our patients had no problems of intracranial hypertension. Although based on different pathophysiological basis as recently emphasized [8, 9], ªCPP managementº and ªLund therapyº imply the importance of assessing pressure autoregulation to guide the therapy. Rosner et al. [1] did not test autoregulation in their study but showed, as indirect evidence of its integrity, an inverse relationship between MAP and ICP during MAP manipulation. Asgeirsson et al. [2] did not test autoregulation but tested CO2 reactivity, which was impaired in all the cases (this was indeed the inclusion criteria). Impairment of CO2 reactivity and pressure autoregulation
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are related to poor outcome; therefore, it is likely that in that patient population pressure autoregulation was also impaired. With this in mind, we hypothesized that norepinephrine could be used to increase blood pressure and stabilize CPP without potentiating hyperemia; we verified that this was true only if autoregulation was preserved. In this study SjO2 was used as an independent measure of the adequacy of perfusion. During norepinephrine infusion in the ten patients with preserved autoregulation, none of the patients became hyperemic according to SjO2 values and this confirmed CBF results. The two patients with impaired autoregulation showed an increase in SjO2 but remained at the upper limit of the normal range [5]. The partial discrepancy between CBF and SjO2 results is not surprising. Recently Cormio et al. [10] reported that in severe HI elevated SjO2 cannot be automatically equated to hyperemia. In the ten patients with preserved autoregulation, the MFV of MCA was within our reference range [5] and remained stable during the test, confirming CBF results. One of the two patients with impaired autoregulation had the highest value. To evaluate pressure autoregulation,
CBF has to be measured. The main limitation is that CBF measurement techniques are not always available in the ICU. SjO2 and TCD seem to be insufficiently sensible to predict hyperemia following norepinephrine infusion. Recently Czosnyka et al. proposed two indexes of cerebrovascular reactivity [11] and autoregulatory reserve [12], which can be obtained by respectively analyzing the relationship between ICP and MAP and MFV of MCA and CPP during spontaneous fluctuations of MAP (or CPP). Both the indexes have prognostic value; further studies are therefore required to ascertain whether these indexes can be used to guide autoregulation-oriented therapy. In conclusion, our data suggest that norepinephrine can be used to increase blood pressure and stabilize CPP without potentiating hyperemia only if autoregulation is preserved. Further studies are required to confirm the importance of orienting therapy according to the pressure autoregulation status of the cerebral circulation. Acknowledgements The authors thank V. M. Ranieri, MD for his helpful criticism.
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