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British Journal of Anaesthesia
BJA

Effects of moderate and severe arterial hypotension on intracerebral perfusion and brain tissue oxygenation in piglets

  • S.K. Ringer
    Correspondence
    Corresponding author.
    Affiliations
    Section of Anaesthesiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
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  • N.G. Clausen
    Affiliations
    Department of Anaesthesiology, University Children's Hospital Zurich, Zurich, Switzerland

    Children's Research Centre, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland

    Department of Anaesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark
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  • N. Spielmann
    Affiliations
    Department of Anaesthesiology, University Children's Hospital Zurich, Zurich, Switzerland

    Children's Research Centre, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland
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  • S. Ohlerth
    Affiliations
    Clinic of Diagnostic Imaging, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
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  • A. Schwarz
    Affiliations
    Section of Anaesthesiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
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  • M. Weiss
    Affiliations
    Department of Anaesthesiology, University Children's Hospital Zurich, Zurich, Switzerland

    Children's Research Centre, University Children's Hospital of Zurich, University of Zurich, Zurich, Switzerland
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Open ArchivePublished:October 09, 2018DOI:https://doi.org/10.1016/j.bja.2018.07.041

      Abstract

      Background

      Hypotension is common in anaesthetised children, and its impact on cerebral oxygenation is unknown. The goal of the present study was to investigate the effects of moderate systemic arterial hypotension (mHT) and severe hypotension (sHT) on cerebral perfusion and brain tissue oxygenation in piglets.

      Methods

      Twenty-seven anaesthetised piglets were randomly allocated to a control group, mHT group, or sHT group. Cerebral monitoring comprised a tissue oxygen partial pressure (PtO2) and laser Doppler (LD) perfusion probe advanced into the brain tissue, and a near-infrared spectroscopy sensor placed over the skin measuring regional oxygen saturation (rSO2). Arterial hypotension was induced by blood withdrawal and i.v. nitroprusside infusion [target MAP: 35–38 (mHT) and 27–30 (sHT) mm Hg]. Data were analysed at baseline, and every 20 min during and after treatment.

      Results

      Compared with control, PtO2 decreased equally with mHT and sHT [mean (SD) after 60 min: control: 17.1 (6.4); mHT: 6.4 (3.6); sHT: 7.2 (4.3) mm Hg]. No differences between groups were detected for rSO2 and LD during treatment. However, in the sHT group, rSO2 increased after restoring normotension [from 49.3 (9.5) to 58.9 (8.9)% Post60]. sHT was associated with an increase in blood lactate [from 1.5 (0.4) to 2.4 (0.9) mmol L−1], and a decrease in bicarbonate [28 (2.4) to 25.8 (2.6) mmol L−1] and base excess [4.7 (1.9) to 2.0 (2.7) mmol L−1] between baseline and 60 min after the start of the experiment.

      Conclusions

      Induction of mHT and sHT by hypovolaemia and nitroprusside infusion caused alterations in brain tissue oxygenation in a piglet model, but without detectable changes in brain tissue perfusion and regional oxygen saturation.

      Keywords

      • Intraoperative hypotension in children may influence cerebral perfusion, but data on this relationship are scarce.
      • This study in piglets focused on the impact of different levels of systemic hypotension on brain tissue oxygenation and perfusion and regional oxygen saturation measured by near-infrared spectroscopy.
      • Intraoperative hypotension during anaesthesia was associated with a decrease in brain tissue oxygenation, which was not detected by cerebral perfusion or regional oxygenation monitoring.
      • This study shows that laser Doppler cerebral perfusion and near-infrared spectroscopy measurements do not correspond with actual brain tissue oxygenation in the case of intraoperative hypotension.
      Hypotension during general anaesthesia in paediatric surgery is a frequently reported event. Nafiu and colleagues
      • Nafiu O.O.
      • Kheterpal S.
      • Morris M.
      • Reynolds P.I.
      • Malviya S.
      • Tremper K.K.
      Incidence and risk factors for preincision hypotension in a noncardiac pediatric surgical population.
      reported an incidence of pre-incisional hypotension in anaesthetised children of 36%, neonates and infants not included. Another study reported a 55% incidence of severe hypotension (sHT) during neonatal anaesthesia.
      • Gorges M.
      • West N.C.
      • Karlsdottir E.
      • Ansermino J.M.
      • Cassidy M.
      • Lauder G.R.
      Developing an objective method for analyzing vital signs changes in neonates during general anesthesia.
      Similarly, moderate hypotension (mHT) has been reported at a rate of 49% during anaesthesia in infants undergoing inguinal herniotomy.
      • McCann M.E.
      • Withington D.E.
      • Arnup S.J.
      • et al.
      Differences in blood pressure in infants after general anesthesia compared to awake regional anesthesia (GAS study-a prospective randomized trial).
      Systemic hypotension during anaesthesia might decrease cerebral perfusion. This is of special concern in infants because of their lower cerebral autoregulatory reserve and developing brain tissue.
      • McCann M.E.
      • Soriano S.G.
      Perioperative central nervous system injury in neonates.
      • McCann M.E.
      • Schouten A.N.
      Beyond survival; influences of blood pressure, cerebral perfusion and anesthesia on neurodevelopment.
      Severe postoperative encephalopathies with cerebral ischaemic lesions shown by magnetic resonance imaging have been reported in infants suffering from blood pressure (BP) fluctuations.
      • McCann M.E.
      • Schouten A.N.
      • Dobija N.
      • et al.
      Infantile postoperative encephalopathy: perioperative factors as a cause for concern.
      Cerebral oxygenation monitoring using near-infrared spectroscopy (NIRS) is increasingly used in paediatric anaesthesia and intensive care medicine.
      • Olbrecht V.A.
      • Skowno J.
      • Marchesini V.
      • et al.
      An international, multicenter, observational study of cerebral oxygenation during infant and neonatal anesthesia.
      Recent studies have revealed a weak association between low systemic blood pressure (BP) and low regional cerebral oxygenation measured by NIRS in infants younger than 6 months.
      • Olbrecht V.A.
      • Skowno J.
      • Marchesini V.
      • et al.
      An international, multicenter, observational study of cerebral oxygenation during infant and neonatal anesthesia.
      • Koch H.W.
      • Hansen T.G.
      Perioperative use of cerebral and renal near-infrared spectroscopy in neonates: a 24-h observational study.
      However, data evaluating intracerebral tissue blood flow and oxygenation during different degrees of hypotension in young children are scarce. The goal of the present study was to investigate the effects of mHT and sHT on invasively measured intracerebral blood flow and tissue oxygenation in a piglet model to increase our understanding of the association between BP and cerebral haemodynamics during anaesthesia.

      Methods

       Study design

      The study was approved by the local Ethics Committee for Animal Experiments (license number ZH175/16) and experiments were performed according to the ARRIVE guidelines. Twenty-seven 3- to 6-week-old female commercial piglets were randomly allocated (picking slips of paper out of an envelope) to three treatment groups: control, mHT, or sHT.

       Anaesthesia

      Piglets were not starved before anaesthesia. Anaesthesia was induced using sevoflurane (Sevorane®; Abbott AG, Baar, Switzerland) in oxygen applied by a facemask. Initial vital sign monitoring included pulse oximetry, ECG, non-invasive BP, and rectal temperature (S/5TM anaesthesia monitor, Datex-Ohmeda, Helsinki, Finland). As soon as sufficient anaesthetic depth was achieved, a peripheral i.v. cannula was placed into the middle auricular vein and midazolam (Dormicum®; Roche Pharma, Reinach, Switzerland) 0.2 mg kg−1 was injected. Tracheas of the piglets were orally intubated with a cuffed tracheal tube and composition of respiratory gases and spirometry were monitored.
      Anaesthesia was maintained using sevoflurane in oxygen and air [inspired oxygen fraction (FiO2) adjusted to obtain haemoglobin (Hb) oxygen saturation (SpO2) ≥97%: 0.21–0.35] combined with midazolam 1 mg kg−1 h−1 i.v. The piglets were artificially ventilated using volume-controlled ventilation with a PEEP of 5 cm H2O. Ventilator settings were adjusted to maintain physiologic arterial partial pressures of carbon dioxide (PaCO2=4.7–6 kPa). Sufficient anaesthesia depth was ensured by clinical judgement of an experienced veterinarian anaesthetist (S.K.R.). The femoral artery was catheterised using a cut down technique (BD Insyte-ATM 22G; Becton Dickinson Infusion Therapy, Systems Inc., Sandy, UT, USA) to monitor arterial BP and for blood withdrawal. A Ringer's acetate infusion containing glucose 1% (Ringeracetat Glucose 1%; Bichsel, Interlaken, Switzerland) was started (5 ml kg−1 h−1) immediately after induction. The maintenance infusion was changed to glucose free Ringer's acetate (Ringer-Acetat Fresenius i.v.; Fresenius Kabi AG, Oberdorf, Switzerland) if the blood glucose concentration was >6 mmol L−1. Hypoglycaemia (blood glucose <3 mmol L−1) was corrected using boli of 50% glucose solution (Glucose-Lösung 50%; AlleMan Pharma GmbH, Pfullingen, Germany).
      Unintended hypotension (MAP<50 mm Hg) was corrected by administering norepinephrine (Noradrenaline Sintetica, Sintetica S.A., Mendrisio, Switzerland) continuous i.v. infusion (started at 0.03 μg kg−1 min−1 and adapted accordingly). The piglets were kept normothermic (38.4–39.5°C) by active warming or cooling.

       Cerebral measurements

      After the administration of an i.v. bolus of fentanyl (10 μg kg−1) (Sintenyl; Sintetica SA) and local infiltration with lidocaine 0.1 ml (Lidocain HCl 2%, Bichsel, Interlaken, Switzerland) and bupivacaine 0.1 ml (Carbostesin 0.5%; AstraZeneca AG, Zug, Switzerland), the piglets were instrumented with two craniotomy bolts. The bolts were drilled and screwed into the frontal bone 1.2–1.3 cm lateral of the midline and 1.5 cm above the level of a horizontal line drawn through the middle of the eyeballs. A PtO2 (Licox® Brain Tissue Oxygen Monitoring, Integra®, Sophia Antipolis, Cedex, France) and a laser Doppler (LD) probe (moorVMSTM-LD blood flow monitor, Moor Instruments, Devon, UK) were advanced through the bolts into the frontal white matter. In all piglets, a single operator performed the procedure (N.G.C.). Correct positioning of the probes was verified with CT in each subject (Fig. 1). Afterwards, an NIRS sensor (OxyAlert® NIRSensor Neonatal, Covidien Inc., Minneapolis, MN, USA) was placed over the skin caudally to the cerebral probes to measure regional cerebral oxygen saturation (rSO2).
      Fig 1
      Fig 1CT image confirming correct probe placement in the frontal lobes. The tissue oxygen partial pressure probe is shown on the left and the laser Doppler probe on the right side of the image.
      Cerebral tissue blood flow (CBF) measured by the LD technique, PtO2, and rSO2 (INVOSTM 5100C Cerebral/Somatic Oximeter, Covidien Inc.) were monitored continuously. Baseline values were recorded in duplicate (20 min apart) 2 h after PtO2 probe placement to verify a stable baseline. After measuring baseline (B) values of vital parameters and extended arterial blood gas analysis [Hb, electrolytes, lactate, glucose, partial pressure of CO2 and O2, pH, bicarbonate (HCO3) and base excess [BE (ecf) (RAPIDPoint® 500; Siemens Healthcare Diagnostics AG, Zurich, Switzerland)], treatments were started.

       Study protocol

      Hypotension was induced by withdrawing blood (10 ml kg−1 body weight over 5 min) via the femoral artery catheter and followed by the use of continuous infusion of nitroprusside (Nitrate® 50 mg, SERB S.A.S., Paris, France) to effect (starting dose 6 μg kg−1 min−1 and adapted as needed). Target MAP values were 35–38 mm Hg (mHT) and 27–30 mm Hg (sHT). Once targets were achieved (Tr0), MAP and anaesthesia were maintained stable for 1 h (Tr0–Tr60). Afterwards, the withdrawn blood volume (groups mHT and sHT) was substituted with balanced hydroxyethyl starch 130/0.4 i.v. (Voluven® 6% balanced, Fresenius Kabi (Schweiz) AG, Oberdorf, Switzerland) and nitroprusside discontinued to return to normotension (MAP>50 mm Hg). Monitoring was continued for an additional hour.
      The piglets were euthanised using a T61 euthanasia solution i.v. (T61 ad us. Vet. MSD Animal Health GmbH, Lucerne, Switzerland) at the end of the procedure.
      Vital sign data, respiratory and anaesthesia gases, CBF, PtO2, and rSO2 were recorded every 5 min. Extended blood gases were obtained at B, after maintaining treatment goals for 1 h (Tr60), and another one 1 h after returning to normotension (Post60). Doppler flow measurements were obtained in non-absolute values and therefore data were analysed as a proportion change compared with baseline (normalised flow) values of each piglet.
      • Hahn G.H.
      • Heiring C.
      • Pryds O.
      • Greisen G.
      Cerebral vascular effects of hypovolemia and dopamine infusions: a study in newborn piglets.

       Statistical analyses

      Data were analysed before (B), during (Tr20, Tr40, Tr60) and after (Post20, Post40, Post60) treatment using IBM® SPSS® Statistics Version 22 (IBM Corp., Zurich, Switzerland) and Graph Pad Prism 5 for Mac OS X software. Kolmogorov–Smirnov and Saphiro–Wilk were used to test for normality distribution. The two baseline measurements (−20B, B) were compared using the Wilcoxon test to verify a stable baseline for PtO2, LD, rSO2, FiO2, and HR. Repeated measures mixed analysis of variance (ANOVA) followed by Sidak post hoc tests were used to investigate changes over time and between groups. One-way ANOVA was used to compare the three treatments regarding age, body weight, and total duration of anaesthesia. All data are presented as mean (standard deviation). A P<0.05 was considered statistically significant.

      Results

      All piglets were in good condition on arrival and completed the treatment as randomised. There were no significant differences among demographics between groups (Table 1). Appropriate positioning of all intracranial probes was confirmed with CT, except the LD-probe of piglet Number 5 (Group sHT), of which data were excluded from analysis.
      Table 1Demographic data [mean (range)] of 27 piglets randomly allocated to three groups: control (C), moderate hypotension (mHT), and severe hypotension (sHT)
      ControlmHTsHTP-value
      Number of animals999
      Age (days)31 (21–41)36 (30–41)35 (26–44)0.28
      Body weight (kg)6.6 (5.4–7.4)6.9 (5.4–8.1)6.2 (5.4–7.0)0.13
      Anaesthesia time (min)339 (295–394)364 (265–524)358 (314–407)0.53
      Breed
       Large White (LW)010
       Swiss Landrace (SL)445
       LW × SL332
       (LW × SL) × Duroc111
       Duroc × LW101
      Norepinephrine was necessary in 77.8% (7/9) of the control piglets, 66.7% (6/9) of the mHT piglets, and 77.8% (7/9) of the sHT piglets to maintain an MAP>50 mm Hg in controls and during the normotensive phases in mHT and sHT animals. Median (range) dosing rates of norepinephrine were 0.04 (0–0.14) (control), 0.04 (0–0.11) (mHT), and 0.05 (0–0.15) (sHT) μg kg−1min−1 with infusion times of 230 (0–260) (control), 90 (0–195) (mHT), and 110 (0–215) (sHT) min. Seven controls, four mHT, and six sHT piglets needed norepinephrine already at baseline. One animal in the sHT group required an i.v. bolus of glucose.
      Nitroprusside was always necessary and had to be constantly adapted to induce and maintain hypotension goals. Dose ranges were 0.31–1.69 and 0.4–3.28 mg kg−1 h−1 to induce mHT and sHT, respectively.
      Changes in blood gases, Hb, electrolytes, lactate, glucose, and respiratory gases are presented in Fig 2, Fig 3. No changes over time or between groups were detected for pH, PaCO2, potassium, chloride, FiO2, and end-tidal sevoflurane (ETsevo). An interaction of time with group was detected for PaO2, HCO3, BE (ecf), and Hb. Within both hypotension groups, an increase in PaO2 was observed during treatment (Tr60) followed by a decrease to baseline values once normotension was restored. A significant decrease in HCO3 and BE (ecf) during treatment was observed for sHT only. Similarly, sHT resulted in a significant increase in lactate at Tr60 compared with B (P=0.003) and to the control (p = 0.016) and mHT groups (P=0.007).
      Fig 2
      Fig 2Mean values for arterial partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2), bicarbonate (HCO3), base excess (BE), haemoglobin (Hb), inspired oxygen fraction (FiO2), and end-tidal sevoflurane (ETsevo) measurements of 27 piglets before (Baseline), 60 min after starting treatment (Tr60), and 60 min after finishing treatment (Post60). Groups: control (C, n=9), moderate hypotension (mHT, MAP=35–38 mm Hg, n=9), severe hypotension (sHT, MAP=27–30 mm Hg, n=9). Data represent mean with standard deviation. *Significantly different compared with baseline of the same group; compared with C group; significant difference compared with sHT. P<0.05.
      Fig 3
      Fig 3Mean values for blood sodium (Na), chloride (Cl), potassium (K), ionised calcium (Ca2+), lactate, and glucose measurements of 27 piglets before (Baseline), 60 min after starting treatment (Tr60), and 60 min after finishing treatment (Post60). Groups: control (C, n=9), moderate hypotension (mHT, MAP=35–38 mm Hg, n=9), severe hypotension (sHT, MAP=27–30 mm Hg, n=9). Data represent mean with standard deviation. *Significantly different compared with baseline of the same group; compared with C group; significant difference compared with sHT. P<0.05.
      A significant interaction of time with group was detected for HR, PtO2, and rSO2 (Fig. 4). HR increased significantly with sHT during treatment and remained elevated. With mHT, HR was higher only after restoring normotension and was never different to controls. No changes in PtO2 were detected over time in the control group. A significant decrease in PtO2 was observed immediately after inducing hypotension with no difference between mHT and sHT. In group sHT but not in group mHT, PtO2 returned to baseline values after restoring normotension. For rSO2, no significant changes over time could be detected for controls and mHT. However, with sHT, a significant increase in rSO2 was detected compared with baseline after restoring normotension. No significant differences between groups at baseline or any other time point were detected. There were significant changes over time independent of treatment detected for CBF with an increase after restoring normotension.
      Fig 4
      Fig 4Mean values for brain tissue oxygen partial pressure (Pto2), regional cerebral oxygen saturation (rSO2), HR, and laser Doppler flow (normalised flow=divided by the baseline value) data from 27 piglets anaesthetised with sevoflurane-midazolam and divided into three groups: nine control (C), nine severe hypotension (sHT), nine moderate hypotension (mHT). Treatment time is marked with a grey bar. −20B and B: baseline, Tr20–Tr60: treatment, Post20–Post60: time after restoring normotension. Data represent mean with standard deviation. *Significantly different compared with baseline of the same group; compared with C group; significant difference with B independent of group. P<0.05. Flow data of group sHT includes only eight piglets.

      Discussion

      This study investigated the effect of moderate and severe systemic hypotension on intracerebral perfusion and brain tissue oxygenation in piglets undergoing general anaesthesia. The main findings were that mHT and sHT caused alterations in brain tissue oxygenation without detectable changes in CBF and rSO2. In addition, a significant increase in blood lactate and a decrease in HCO3 and BE (ecf) were observed during sHT.
      The effect of anaesthesia related hypotension on cerebral oxygenation and blood flow has been investigated in children using NIRS and transcranial Doppler (TCD).
      • Michelet D.
      • Arslan O.
      • Hilly J.
      • et al.
      Intraoperative changes in blood pressure associated with cerebral desaturation in infants.
      • Rhondali O.
      • Juhel S.
      • Mathews S.
      • et al.
      Impact of sevoflurane anesthesia on brain oxygenation in children younger than 2 years.
      • Rhondali O.
      • Mahr A.
      • Simonin-Lansiaux S.
      • et al.
      Impact of sevoflurane anesthesia on cerebral blood flow in children younger than 2 years.
      • Rhondali O.
      • Pouyau A.
      • Mahr A.
      • et al.
      Sevoflurane anesthesia and brain perfusion.
      In agreement with our results, other authors found a poor association between BP and rSO2 in human neonates and infants aged less than 6 months.
      • Olbrecht V.A.
      • Skowno J.
      • Marchesini V.
      • et al.
      An international, multicenter, observational study of cerebral oxygenation during infant and neonatal anesthesia.
      • Koch H.W.
      • Hansen T.G.
      Perioperative use of cerebral and renal near-infrared spectroscopy in neonates: a 24-h observational study.
      However, and contrary to our results, studies in infants and children suggest a decrease in CBF based on rSO2 when the MAP is below a certain threshold.
      • Michelet D.
      • Arslan O.
      • Hilly J.
      • et al.
      Intraoperative changes in blood pressure associated with cerebral desaturation in infants.
      • Rhondali O.
      • Juhel S.
      • Mathews S.
      • et al.
      Impact of sevoflurane anesthesia on brain oxygenation in children younger than 2 years.
      TCD used in children younger than 6 months demonstrated a reduction in CBF velocity when MAP was equal to or below 38 (9) mm Hg.
      • Rhondali O.
      • Mahr A.
      • Simonin-Lansiaux S.
      • et al.
      Impact of sevoflurane anesthesia on cerebral blood flow in children younger than 2 years.
      The same authors analysed data of previous studies
      • Rhondali O.
      • Juhel S.
      • Mathews S.
      • et al.
      Impact of sevoflurane anesthesia on brain oxygenation in children younger than 2 years.
      • Rhondali O.
      • Mahr A.
      • Simonin-Lansiaux S.
      • et al.
      Impact of sevoflurane anesthesia on cerebral blood flow in children younger than 2 years.
      retrospectively and concluded that at MAP<35 mm Hg, cerebral metabolic reserve is low and further changes might be poorly tolerated by the brain.
      • Rhondali O.
      • Pouyau A.
      • Mahr A.
      • et al.
      Sevoflurane anesthesia and brain perfusion.
      The current study is the first one investigating the effects of hypotension on cerebral perfusion and oxygenation using intracranial tissue oxygenation and tissue blood flow probes, combined with NIRS monitoring. Based on previous research, the observed decrease in PtO2 with no concomitant decrease in CBF and rSO2 during hypotension was unexpected. Cerebral autoregulation combined with a vasodilatory effect of sevoflurane might have been sufficient to maintain CBF despite a decrease in systemic MAP in our piglets.
      • Rhondali O.
      • Juhel S.
      • Mathews S.
      • et al.
      Impact of sevoflurane anesthesia on brain oxygenation in children younger than 2 years.
      However, a hypotension associated decrease in CBF has previously been observed using TCD in sevoflurane anaesthetised children.
      • Rhondali O.
      • Mahr A.
      • Simonin-Lansiaux S.
      • et al.
      Impact of sevoflurane anesthesia on cerebral blood flow in children younger than 2 years.
      Intracranial LD flowmetry measures local erythrocyte flow velocity in the microvasculature
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      • Heiring C.
      • Pryds O.
      • Greisen G.
      Applicability of near-infrared spectroscopy to measure cerebral autoregulation noninvasively in neonates: a validation study in piglets.
      and might not be comparable with more global CBF measurements using TCD (over the middle cerebral artery).
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      • et al.
      A comparison study of cerebral autoregulation assessed with transcranial Doppler and cortical laser Doppler flowmetry.
      However, TCD and cortical LD flow have been shown to correlate during haemorrhagic shock in rabbits.
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      Cerebral blood flow and resistances during hypotensive haemorrhage in the rabbit: transcranial Doppler and laser-Doppler flowmetry.
      Although normally positioned outside the dura mater, in the present study the LD probe was advanced into the white matter in order to assess flow in the same cerebral tissue layer as the PtO2 probe. The insertion of the probe itself into the brain tissue might have caused local disturbance of blood flow.
      A decrease in PtO2 was detected during mHT and sHT despite no decrease in CBF. Brain PtO2 is influenced by the local balance between oxygen delivery (DO2) and the cerebral metabolic rate of oxygen (CMRO2).
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      Oxygen delivery to the brain is determined by CBF and oxygen content of blood (CaO2). However, no differences in CBF or factors affecting CaO2 (Hb and fraction of oxygenated Hb measured by co-oximetry) were detected between the groups. An increase in the CMRO2 could not be expected as anaesthetic depth was maintained constant and because nitroprusside is unlikely to increase cerebral oxygen metabolism.
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      • et al.
      Cerebrovascular effects of sodium nitroprusside in the anaesthetized baboon: a positron emission tomographic study.
      However, PtO2 could also have decreased as a result of increased arteriovenous shunting induced by nitroprusside. Nitroprusside is a potent vasodilatory drug with a direct effect on cerebral blood vessels.
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      • Touzani O.
      • Young A.R.
      • et al.
      Cerebrovascular effects of sodium nitroprusside in the anaesthetized baboon: a positron emission tomographic study.
      Coinciding with our results, a decrease in PtO2 during nitroprusside-induced hypotension has been described in pigs (40 kg) and dogs.
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      Sodium nitroprusside compared with isoflurane-induced hypotension: the effects on brain oxygenation and arteriovenous shunting.
      Also in agreement with our results, nitroprusside does not produce a simultaneous decrease, but rather an increase in CBF.
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      • Touzani O.
      • Young A.R.
      • et al.
      Cerebrovascular effects of sodium nitroprusside in the anaesthetized baboon: a positron emission tomographic study.
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      • Koenig H.M.
      Sodium nitroprusside compared with isoflurane-induced hypotension: the effects on brain oxygenation and arteriovenous shunting.
      The observed changes in PtO2, but not in rSO2 and LD flow, can therefore be explained by a preserved CBF but an increased arteriovenous shunting because of nitroprusside. The increased shunting might have led to inadequate capillary perfusion and consequent local tissue hypoxia despite maintained regional CBF. Coinciding with our results, using magnetic resonance imaging in an identical piglet model of hypotension, no changes in CBF could be detected despite signs of metabolic disturbances.
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      • et al.
      Effects of hypotension and/or hypocapnia during sevoflurane anesthesia on perfusion and metabolites in the developing brain of piglets—a blinded randomized study.
      The observed increase in blood lactate during sHT in our study might have been a consequence of tissue hypoxia because of decreased capillary perfusion after arteriovenous shunting.
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      • Edelman G.
      • Ripper R.
      • Koenig H.M.
      Sodium nitroprusside compared with isoflurane-induced hypotension: the effects on brain oxygenation and arteriovenous shunting.
      Despite a decrease in PtO2 and possible tissue hypoxia during hypotension, no decrease in oxygen saturation was detected by NIRS. Coinciding with our results, only a weak correlation was described between rSO2 and PtO2 in piglets subjected to hypoxemia during extracorporeal membrane oxygenation.
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      • Tyree M.
      • DiGeronimo R.
      Correlation of brain tissue oxygen tension with cerebral near-infrared spectroscopy and mixed venous oxygen saturation during extracorporeal membrane oxygenation.
      Also, in patients with traumatic brain injury, NIRS did not accurately reflect PtO2 measurements.
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      • Cayuela A.
      • Arellano-Orden V.
      • et al.
      Invasive and noninvasive assessment of cerebral oxygenation in patients with severe traumatic brain injury.
      This can be explained by the fact that cerebral NIRS is a non-invasive monitor of global brain oxygenation and is largely determined by the venous component (75%).
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      • Arango M.
      Near-infrared spectroscopy as an index of brain and tissue oxygenation.
      Therefore, comparable with mixed venous oxygen saturation, changes in rSO2 reflect ERO2 (i.e. changes in the ratio of oxygen consumption to DO2). It is important to note that NIRS measures intravascular Hb oxygen saturation rather than oxygenation at the tissue level. Consequently, rSO2 might not always reflect real-time cerebral tissue oxygen tension. This is comparable with patients with septic shock, demonstrating a maintained or elevated mixed venous oxygen saturation and high cardiac output values despite tissue hypoxia, because of altered microcirculation as a result of arteriovenous shunting.
      • Spronk P.E.
      • Zandstra D.F.
      • Ince C.
      Bench-to-bedside review: sepsis is a disease of the microcirculation.
      In accordance with previous reports, there seems to be a correspondence between LD flow measurements and NIRS.
      • Lee J.K.
      • Brady K.M.
      • Mytar J.O.
      • et al.
      Cerebral blood flow and cerebrovascular autoregulation in a swine model of pediatric cardiac arrest and hypothermia.
      An ‘overshoot’ of tissue oxygen has been described after tissue hypoxia and might be the reason for an increased rSO2 and CBF after discontinuing hypotension in our piglets.
      • Manley G.T.
      • Pitts L.H.
      • Morabito D.
      • et al.
      Brain tissue oxygenation during hemorrhagic shock, resuscitation, and alterations in ventilation.
      This effect has been attributed to altered cellular oxygen utilisation after tissue hypoxia.
      • Manley G.T.
      • Pitts L.H.
      • Morabito D.
      • et al.
      Brain tissue oxygenation during hemorrhagic shock, resuscitation, and alterations in ventilation.
      The ‘overshoot’ of tissue oxygen seems to be more pronounced after sHT, as shown by a significant immediate increase in PtO2 once returned to normotension.
      The increase in PaO2 during hypotension was unexpected, as nitroprusside is assumed to eliminate hypoxic pulmonary vasoconstriction and therefore rather increase venous admixture and decrease PaO2.
      • Mollhoff T.
      • Van Aken H.
      • Mulier J.P.
      • Muller E.
      • Lauwers P.
      Effects of urapidil, ketanserin and sodium nitroprusside on venous admixture and arterial oxygenation following coronary artery bypass grafting.
      A limitation of the study is the use of a piglet model to investigate tissue oxygenation and perfusion during paediatric anaesthesia-related hypotension. However, it would be unethical to subject children to hypotension and piglets seem to be an appropriate model to investigate anaesthesia associated brain complications.
      • Whitaker E.E.
      • Bissonnette B.
      • Miller A.D.
      • et al.
      A novel, clinically relevant use of a piglet model to study the effects of anesthetics on the developing brain.
      The use of nitroprusside to mimic hypotension during clinical anaesthesia is probably not ideal. However, piglets need high concentrations of sevoflurane to remain anaesthetised and it would have been impossible to induce sHT by merely increasing sevoflurane concentration. In order to keep Hb concentrations comparable between groups, it was decided not to further exsanguinate the piglets. Only female piglets were included into the study in order to rule out the influence of sex and because male piglets at that age had already undergone anaesthesia for castration. However, it needs to be considered that there is evidence that vulnerability to anaesthesia associated neurotoxicity and in general to harsh conditions is influenced by gender.
      • Zarulli V.
      • Barthold Jones J.A.
      • Oksuzyan A.
      • et al.
      Women live longer than men even during severe famines and epidemics.
      In conclusion, both mHT and sHT induced by nitroprusside decrease cerebral PtO2 while maintaining CBF in piglets. A decrease in cerebral PtO2 can occur despite maintained CBF and CaO2. NIRS did not detect changes in PtO2 during unaltered cerebral tissue perfusion in piglets. Surprisingly, no decrease in CBF was detected despite severe systemic hypotension accompanied by increased blood lactate.

      Authors' contributions

      Study design/planning: S.K.R., N.G.C., S.O., M.W.
      Implementation of the study: S.K.R., N.G.C., N.S., S.O., A.S.
      Data analysis: S.K.R., N.G.C., M.W.
      Statistical analysis together with a statistician from the University of Zurich: S.K.R.
      Writing and reviewing of the manuscript and approval of the final version: all authors.

      Acknowledgements

      The authors thank Siemens Healthcare Diagnostics AG (Zurich, Switzerland) for providing the blood gas analyses kits. We further acknowledge Medtronic Schweiz AG (Münchenbuchsee, Switzerland) and Integra LifeSciences (Lausanne, Switzerland) for providing the monitors during the trials.

      Declaration of interest

      The authors declare that they have no conflicts of interest.

      Funding

      Anna Mueller Grocholski-Foundation , Zurich, with a research grant (2016).

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