Authors: Niels D. Olesen, Astrid H. Egesborg, Hans-Jørgen Frederiksen, Carl-Christian Kitchen, Lars B. Svendsen, Niels V. Olsen, Niels H. Secher
Categories: Original Article, Anesthesia, carotid artery, cerebrovascular circulation, hypotension
Source: Journal of Anaesthesiology, Clinical Pharmacology
Anesthesia often reduces mean arterial pressure (MAP) to a level that may compromise cerebral blood flow. We evaluated whether phenylephrine treatment of anesthesia-induced hypotension affects internal carotid artery (ICA) blood flow and whether anesthesia affects ICA flow and CO2 reactivity.
The study included twenty-seven patients (65 ± 11 years; mean ± SD) undergoing esophageal resection (n = 14), stomach resection (n = 12), or a gastroentero anastomosis (n = 1) during combined propofol-remifentanil and thoracic epidural anesthesia. Duplex ultrasound evaluated ICA blood flow. Evaluations were before and after induction of anesthesia, before and after the administration of phenylephrine as part of standard care to treat anesthesia-induced hypotension at a MAP below 60 mmHg, and the hypocapnic reactivity of ICA flow was determined before and during anesthesia.
Induction of anesthesia reduced MAP from 108 ± 12 to 66 ± 16 mmHg (P < 0.0001) and ICA flow from 340 ± 92 to 196 ± 52 mL/min (P < 0.0001). Phenylephrine was administered to 24 patients (0.1–0.2 mg) and elevated MAP from 53 ± 8 to 73 ± 8 mmHg (P = 0.0001) and ICA flow from 191 ± 43 to 218 ± 50 mL/min (P = 0.0276). Furthermore, anesthesia reduced the hypocapnic reactivity of ICA flow from 23 (18–33) to 14%/kPa (10–22; P = 0.0068).
Combined propofol–remifentanil and thoracic epidural anesthesia affect ICA flow and CO2 reactivity. Phenylephrine partly restored ICA flow indicating that anesthesia-induced hypotension contributes to the reduction in ICA flow.
Keywords: Anesthesia, carotid artery, cerebrovascular circulation, hypotension
Propofol reduces cerebral blood flow (CBF) by approximately 50% by lowered neuronal activity with maintained cerebral O2 extraction fraction.[1,2] Also, propofol anesthesia reduces mean arterial pressure (MAP)[2,3] but it is unknown to what extent the reduction in CBF by propofol anesthesia is aggravated by a low MAP. According to the intraoperative goals, vasoactive medication should be considered if MAP decreases to below, e.g. 60 mmHg, or below 80% of the value before induction, in order to maintain organ blood flow.[4] However, MAP may also be kept low during the so-called hypotensive anesthesia in order to reduce surgical bleeding.[5]
We evaluated internal carotid artery (ICA) flow non-invasively by duplex ultrasound. In patients undergoing combined propofol–remifentanil and thoracic epidural anesthesia, we evaluated the effect of induction of anesthesia on ICA flow and whether ICA flow is affected by hypotension. The primary outcome was the effect on ICA flow by the administration of phenylephrine when MAP decreased to below 60 mmHg. We hypothesized that an increase in MAP would elevate ICA flow. The arterial CO2 tension (PaCO2) is a potent cerebral vasodilator[6] although hypotension appears to attenuate cerebral CO2 reactivity.[7] Thus, the CO2 reactivity of the ICA was determined before and after induction of anesthesia, and ICA flow was ‘corrected’ for eventual changes in PaCO2.
Thirty consecutive patients, planned for open esophageal or stomach resection, aged ≥18 years were recruited for the study after providing written informed consent between December 2016 and July 2017. Ethical approval for the study was provided by the Ethical Committee E of the Capital Region (Videnskabsetiske Komité E for Region Hovedstaden, Kongens Vænge 2, DK-3400, Hillerød, Denmark; Chairperson: Cecilie Mejer Hjelm; October 18, 2016; protocol H-16036250) in accordance with the Declaration of Helsinki. This manuscript adheres to the applicable STROBE guideline. The conduct of the study and the safety of the patients were overseen by the authors. Preoperative hypertension was defined by medical history and treatment with antihypertensive medication. Exclusion criteria were inadequate visualization of the ICA, e.g., due to high bifurcation, above 15% obstruction of either ICA as evaluated by duplex ultrasound prior to inclusion, and neurologic disease considered to affect CBF including dementia, epilepsy, and stroke. Data from this study on the effect of a so-called mesenteric traction syndrome, in response to surgical manipulation of the viscera, on central hemodynamics and ICA flow will be published elsewhere.
No premedication was administered and surgery was after an overnight fast with the patients allowed to drink “clear” fluids until 2 h before the operation. A catheter was inserted in the left radial artery under the cover of local anesthesia. Also, under cover of local anesthesia, an epidural catheter was placed (T8-T10) and 15–30 mg bupivacaine administered followed by infusion of bupivacaine with morphine (2.5 and 0.05 mg/mL; 5 mL/h) and an hourly 15 mg bolus dose bupivacaine. Induction of anesthesia was by propofol with cisatracurium or suxamethonium for muscle relaxation and anesthesia was maintained by propofol and remifentanil. A tracheal tube was placed and ventilation aimed at maintaining an end-tidal CO2 tension (PetCO2) at the pre-anesthesia level (Dräger Primus, Drägerwerk, Lübeck, Germany). Guided by ultrasound, a central venous catheter was inserted through the internal jugular vein contralateral to the ICA insonation site. Blood volume was supported by lactated Ringer’s solution and human albumin 5%. An anesthesia-induced reduction in MAP to below 60 mmHg was treated by bolus dose administration of phenylephrine or ephedrine or infusion of noradrenaline on the choice of the anesthesiologist as part of routine care.
Radial artery pressure derived stroke volume, cardiac output (CO), and total peripheral resistance by modified pulse-contour analysis (Finometer, Finapres Medical Systems, Amsterdam, The Netherlands). The ICA flow was evaluated by duplex ultrasound using a linear transducer at 8–12 MHz (Logiq E, transducer 12L, GE Medical System, Jiangsu, China). The left or right ICA was chosen for insonation according to image quality, i.e. low carotid bifurcation and absence of torsion. The head was turned to the contralateral side and the evaluation was conducted at least 1.5 cm distal to the bifurcation with an insonation angle ≤60° and pulsed-wave Doppler determined the angle-corrected time-averaged maximum blood velocity that corresponds to twice the mean velocity.[8] The mean of two to three recordings over approximately 20 s is reported. Software determined the vessel diameter (Brachial Analyzer for Research v. 6, Medical Imaging Applications LLC, Coralville, IA, USA) and flow was calculated as[8]:
ICA blood flow = π * (diameter/2)^2^ * (Time-averaged maximum blood velocity)/2
and conductance was ICA flow/MAP. The ICA flow was evaluated by a single ultrasonographer. Still images of the duplex ultrasound evaluation in a representative patient are presented in Figure 1.
Figure 1 Duplex ultrasound images from a representative patient. Pulsed-wave evaluation of ICA time-averaged maximum blood velocity (a) and evaluation of ICA diameter using automated wall-tracking software (b)
Near-infrared spectroscopy determined forehead oxygenation (ScO2) on the left side and right deltoid muscle oxygenation (SmO2) (INVOS 5100C, Somanetics, Troy, MI, USA) while laser Doppler flowmetry evaluated forehead skin blood flow and oxygenation at a depth of 1–2 mm close to the hairline (VMS-LDF and VMS-OXY, Moor Instruments, Axminster, UK). Depth of anesthesia was evaluated by the Bispectral index (BIS; BIS Complete Monitoring Systems, Covidien, USA).
Central hemodynamic and skin variables were sampled at 100 Hz (Powerlab, ADInstruments, Bella Vista, Australia) and ScO2, SmO2, and BIS every 5 s on a PC with values averaged over 2 min. Immediately following the evaluation of ICA flow, arterial blood was sampled in pre-heparinized syringes (QS50, Radiometer, Copenhagen, Denmark) and analyzed for blood gas variables (ABL 725, Radiometer). For patients undergoing esophageal resection, measurements were conducted before one-lung ventilation. Evaluation of MAP, HR, and ventilatory parameters were a part of standard of care.
The experimental protocol is presented in Figure 2. Evaluations were conducted at rest breathing room air, following intubation, during anesthesia-induced hypotension at a MAP below 60 mmHg when the anesthesiologist considered to administer 0.1–0.2 mg phenylephrine as part of standard care, and 3–5 min after administration. No attempt was made to reduce MAP deliberately (by, e.g., vasodilators). Cerebral CO2 reactivity was evaluated by hyperventilation when the patients were awake and re-evaluated 60 min after incision and then, in random order, included both hypo-, normo-, and hyperventilation. The changes in ventilation were guided by an increase or a decrease in PetCO2 by 1.5 kPa as evaluated by a face mask, and on the ventilator, respectively, and measurements were conducted after the value had been stable for 5 min. The only interventions conducted as part of the study were the changes in ventilation in order to evaluate CO2 reactivity.
Figure 2 Experimental protocol. Evaluation of ICA flow and arterial gas variables are denoted by *. Evaluations during hypo-, normo-, and hyperventilation during anesthesia were conducted in random order
The minimal clinically important difference in ICA flow by phenylephrine treatment of hypotension was estimated to be 10% based on an association between near-infrared spectroscopy determined reduction in ScO2 by 10% and postoperative cognitive dysfunction.[9] A sample size calculation suggested that 27 patients were needed to detect a difference in ICA flow by 10% at a 5% significance level with a power of 80%.[10]
The primary outcome was the change in ICA flow by phenylephrine treatment of hypotension. Secondary outcomes were (1) the change in ICA flow by induction of anesthesia and (2) the change in hypocapnic ICA CO2 reactivity by anesthesia.
Analysis of variables at the time at rest before induction, after induction of anesthesia, and before and after the administration of phenylephrine was by a repeated measure mixed model, fit by restricted maximum likelihood in a structured covariance model by compound symmetry, with time point as a fixed effect and the subject variable as a random effect and if significant, we evaluated changes from when the patients were awake and in response to phenylephrine (PROC MIXED; SAS 9.4, SAS Institute, Cary, NC, USA). Correction for multiple testing was by the Tukey–Kramer method. As the results may be confounded by hypertension, we also evaluated whether changes in MAP and ICA flow were similar for normo- and hypertensive patients by adding an interaction factor post-hoc. Analysis of plasma lactate concentration was after logarithmic transformation in order to obtain a normal distribution to allow for parametric tests. For the fraction of inspired oxygen, BIS, and the infusion rate of propofol and remifentanil, the change from before to after phenylephrine was evaluated by a Wilcoxon signed-rank test.
The ICA CO2 reactivity was calculated as the change in flow 100/change in PaCO2 baseline flow and similarly for ScO2. The ICA flow and conductance and ScO2 during anesthesia were ‘corrected’ for changes in PaCO2 from the value at rest by the individually determined CO2 reactivity to hypo- and hypercapnia during anesthesia as evaluated by linear regression. Comparison of ICA hypocapnic reactivity when patients were awake and during anesthesia was by a linear mixed model fit by restricted maximum likelihood with the change in ICA flow as the outcome and the fixed effect was the change in PaCO2 with an interaction factor for the difference and the subject variable as a random effect.
The intraclass correlation coefficient for intrarater reliability of ICA flow measurements was evaluated by two-way mixed models (model 3,1) with an absolute agreement for average measures (SPSS 25, Corp. 2013, Armonk, NY). Values are presented as mean ± SD or median (IQR) for not normally distributed data with changes reported as mean (95% CI) and statistical significance was set at P < 0.05.
Fourteen patients underwent esophageal and 12 patients stomach resection, while surgery for one patient was gastroentero anastomosis due to carcinosis [Table 1]. Three patients were excluded from the analysis because the central venous catheter was placed at the chosen insonation side, due to the use of sevoflurane, or because the CO2 reactivity was not evaluated due to early one-lung ventilation. For one patient, the evaluations were not conducted when he was awake and after intubation. Thirteen patients were hypertensive and treated with one, two to three drugs (n = 6, 4, and 1, respectively). Duration of anesthesia and surgery and fluid balance are presented in Table 2. No patient received red blood cells during the study period. The length of stay in hospital was 9 days (8–10) and there was no mortality within 1 month.
When the patients were awake, hyperventilation reduced PaCO2 from 5.0 ± 0.5 to 3.9 ± 0.8 kPa while during anesthesia, PaCO2 was 5.3 ± 0.6 kPa and reduced to 4.1 ± 0.7 kPa and elevated to 6.4 ± 0.5 kPa for the evaluation of CO2 reactivity. The hypocapnic ICA CO2 reactivity was 23%/kPa (18–33) when the patients were awake and decreased to 14%/kPa (10–22; P = 0.0068) during anesthesia while the hypercapnic reactivity was 24%/kPa (15–33). The CO2 reactivity for ScO2 to hypocapnia when the patients were awake was 3.6%/kPa (2.4–5.3) and similar 3.6%/kPa (1.1–5.6; P = 0.7223) during anesthesia while the hypercapnic reactivity was 4.3%/kPa (1.0–6.9).
Induction of anesthesia reduced MAP, heart rate, stroke volume, and thus, CO whereas total peripheral resistance remained unaffected at a BIS of 42 ± 11 [Table 3]. After tracheal intubation, 16 patients had received 0.2 mg (0.2–0.3) phenylephrine, 16 patients 10 mg (10–20) ephedrine while 5 patients had received no vasopressors. The ICA blood velocity was reduced with a stable diameter, and thus, the flow decreased by 144 mL/min (95% CI: 121–168; P < 0.0001) resulting in no change in vascular conductance. Induction of anesthesia did not affect ScO2, skin blood flow, and skin oxygenation whereas SmO2 increased. Additionally, PaCO2 and PaO2 increased while arterial hemoglobin and O2 content decreased with no significant change in plasma lactate concentration.
The evaluation before and after treatment of hypotension by 0.1 mg (0.1–0.2) phenylephrine was conducted for 24 patients, before (n = 15) or after (n = 9) incision while the level of anesthesia was maintained. The MAP had been below 60 mmHg for 4 min (1–6). The effect of phenylephrine was not evaluated in three subjects because one patient did not receive any sympathomimetic drugs while for two patients MAP was maintained by noradrenaline. At the evaluation during hypotension, the accumulated vasopressor administration had been 0.3 mg (0.2–0.4) phenylephrine for 19 patients and 20 mg (10–20) ephedrine for 19 patients, while two patients had received no vasopressors, and none had received noradrenaline. Before administration of phenylephrine, ICA conductance was increased while ScO2 was reduced as compared to when the patients were awake. Phenylephrine increased MAP and total peripheral resistance, while heart rate, stroke volume, and CO were unaffected. Changes in ICA blood velocity and diameter did not reach statistical significance, while ICA flow increased by 27 mL/min (95% CI: 3–51; P = 0.0276) with a reduction in conductance independent of correction for the small changes in PaCO2. There was no significant change in ScO2, SmO2, skin variables, PaCO2, PaO2, arterial hemoglobin or O2 content, plasma lactate concentration, or BIS in response to phenylephrine, while the fraction of inspired O2 increased marginally.
As compared between the normo- and hypertensive patients, MAP was similar when the patients were awake (104 ± 13 vs. 111 ± 10 mmHg; P = 0.4812) and MAP was affected similarly by induction of anesthesia and by phenylephrine (P = 0.3005 for the interaction) with similar changes also in ICA flow (P = 0.9965 for the interaction). The intraclass correlation coefficient for intrarater reliability for the two to three measurements at each time point was 0.98 (95% CI: 0.97–0.99).
This study evaluated whether treatment of hypotension attenuates the anesthesia-induced reduction in ICA flow. In middle-aged and elderly patients of whom approximately half were hypertensive, combined propofol–remifentanil and thoracic epidural anesthesia lowered MAP and reduced ICA flow by about 40%. Most of the reduction in ICA flow in response to anesthesia was likely due to a reduction in cerebral metabolism as there was little change in ScO2. Yet, phenylephrine treatment of anesthesia-induced hypotension at a MAP below 60 mmHg partly restored ICA flow as observed by a 15% increase. Thus, about 20% of the reduction in ICA flow induced by anesthesia appears to be in consequence of a low MAP as phenylephrine has no direct effect on CBF,[10] and the blood–brain barrier seems to be preserved by propofol.[11]
Intraoperative cerebral hypoperfusion is of interest because postoperative cognitive dysfunction and delirium are common following major surgery, particularly in the elderly, and may relate to intraoperative hypotension[12] although that is not a universal finding.[13] Cerebral autoregulation is often considered to maintain CBF when MAP is kept between 60 and 150 mmHg.[14] However, CBF may be affected by a reduction in MAP even within the autoregulatory range[15] and it is unclear whether propofol affects the lower limit of cerebral autoregulation. A previous study demonstrated a 15% increase in ICA flow along with an increase in CO in response to a noradrenaline-induced elevation in MAP from 60–65 to 80–85 mmHg during major abdominal surgery during combined propofol–remifentanil and thoracic epidural anesthesia.[16] Combined with the findings of the present study, the results suggest that ICA flow is somewhat pressure passive with no clear lower limit of cerebral autoregulation. In the present study, induction of anesthesia attenuated CO and that may have contributed to the reduction in ICA flow.[17] In contrast to noradrenaline,[16] phenylephrine did not affect CO, possibly due to the beta-adrenergic effect of noradrenaline whereas phenylephrine is solely an alpha-adrenergic agonist. When the central blood volume and CO are reduced, SmO2 becomes affected before any change in MAP,[18] but in this study, SmO2 in addition to skin blood flow was maintained, indicating that CO was sufficient to secure oxygenation of tissues that are not autoregulated. Thus, the effect of phenylephrine on ICA flow was despite a low CO while PaCO2 and the administration of propofol and remifentanil were unchanged.
It remains to be evaluated whether the observed 15% increase in ICA flow by phenylephrine is clinically important. The ScO2 was reduced during hypotension but remained low when MAP was restored by phenylephrine, possibly due to cutaneous vasoconstriction.[19] Hypotensive anesthesia is reported to be associated with an increase in markers of neuronal damage[20] but studies have probably been too small to detect an effect on the incidence of cognitive dysfunction.[21] During carotid endarterectomy in halothane-N2O anesthesia, the acute critical lower level of regional CBF is reported at a two-thirds reduction at 18 mL/(100 g * min),[22] but the critical level is not known during propofol anesthesia. Propofol reduces CBF and cerebral metabolism similarly[2] and for resting subjects, a reduction in CBF by 30% provokes symptoms associated with cerebral hypoperfusion.[23] Postoperative cognitive complications could reflect prolonged relative cerebral hypoperfusion but that relation is not evaluated, and in addition to hypotension, cognitive complications may relate to hypoxia, drug-related effects, cerebral microemboli, inflammation, and other factors.[24] Future studies could evaluate the effect of maintaining MAP at different absolute or relative levels, using different vasopressors, on the risk of postoperative complications including cognitive dysfunction.
Propofol reduces CBF by about 40%[1-3,17] while epidural anesthesia[25] and remifentanil[26] are reported to reduce MAP with no effect on CBF. Similarly, we found that ICA flow was reduced by approximately 40% by propofol–remifentanil and epidural anesthesia at a BIS of about 40. The cerebral CO2 reactivity, as determined by transcranial Doppler, appears unaffected by propofol,[6] although a reduction is also reported.[1] Here, the cerebral CO2 reactivity was reduced during anesthesia which may reflect the low MAP as hypotension appears to reduce vessel reactivity.[7]
The study was not designed to evaluate a difference between normo- and hypertensive patients. Chronic arterial hypertension may lower cerebral CO2 reactivity[27] and elevate the limits for cerebral autoregulation although less so when hypertension is treated[28] and the preoperative MAP was similar among normo- and hypertensive patients. The sample size calculation was based on an association between near-infrared spectroscopy determined cerebral deoxygenation and postoperative cognitive dysfunction,[9] however, changes in CBF and ScO2 differ in response to different interventions.[19] The evaluation of ICA flow using duplex ultrasound is similar to, and correlates with, an evaluation by phase-contrast magnetic resonance imaging, albeit with large individual variability.[29] Cerebral autoregulation allows for regulation of CBF within 10 s after a change in MAP[30] whereby we consider ICA flow to have reached a steady-state 3–5 min after the administration of phenylephrine. The ICA has no extracranial branches and supplies about 80% of CBF[10] while the remainder is provided by the vertebral artery that was not evaluated. The reactivity of the intracerebral vessels may differ from that of the ICA whereby hypotension could affect regional CBF differently in different areas of the brain and the vertebral artery presents different regulation than that of the ICA.[31] Yet, propofol decreases regional flow throughout the brain.[2] In order to avoid severe hypotension, most patients had received vasopressors and that may have affected the results. Further, the administration of phenylephrine was not controlled. The effect of phenylephrine was evaluated after incision for some patients and surgical stimulation may increase regional neuronal activity and CBF, but we take the effect of surgery to be small as the increase in regional CBF is attenuated by propofol–remifentanil anesthesia combined with regional anesthesia.[32] The study would be improved by evaluation of internal jugular venous bulb O2 saturation and only reactivity to hypocapnia was evaluated when the patients were awake. Although ventilation aimed at the PetCO2 as established when the patients were awake, PaCO2 was slightly higher after induction of anesthesia but changes in ICA flow were similar with and without correction for the small change in PaCO2.
Propofol–remifentanil combined with thoracic epidural anesthesia reduced the ICA CO2 reactivity and ICA flow by about 40%, but phenylephrine treatment of anesthesia-induced hypotension restored about 20% of the reduction in ICA flow. The results indicate that part of the reduction in ICA flow in response to anesthesia is related to a reduction in MAP to below 60 mmHg.
Videnskabsetiske Komité E for Region Hovedstaden, DK-3400, Hillerød, Denmark; Chairperson: Cecilie Mejer Hjelm; October 18^th^ 2016; protocol H-16036250.
The study was preregistered at clinicaltrials.gov. NCT02951273; principal N.D.O.; November 1, 2016. https://clinicaltrials.gov/ct2/show/NCT02951273? term=NCT02951273&rank=1
This study was supported by University of Copenhagen. The funding source had no involvement in study design, collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.
There are no conflicts of interest.
For their invaluable help we thank the surgical and anesthetic personnel at the departments of Anesthesia and Surgical Gastroenterology, Rigshospitalet, Copenhagen, Denmark.