For Peer Review

Intraoperative changes in blood pressure associated with

cerebral desaturation in infants

Journal: Pediatric Anesthesia

Manuscript ID: PAN-2015-0004.R2

Wiley - Manuscript type: Original Paper

Date Submitted by the Author: 24-Mar-2015

Complete List of Authors: Michelet, Daphné; Robert Debré Hospital, Anesthesia Arslan, Ozkan; Robert Debré Hospital, Anesthesia Hilly, Julie; Robert Debré University Hospital, Anesthesiology Mandalsuren, Nyamjargal; Robert Debré Hospital, Anesthesia BRASHER, Christopher; Robert Debré University Hospital, Anestheiology Grace, Robert; Cairns Hospital, Anesthesiology Bonnard, Arnaud; Robert Debré Hospital, Surgery malbezin, serge; Robert Debré University Hospital, Department of Anesthesiology and Intensive Care Nivoche, Yves; Hôpital Robert Debré, Service d’anesthésie réanimation Dahmani, Souhayl; Robert Debre Hospital, Anaesthesiology

Key Words: infant < Age, adverse events < Complications, stroke < Neurological disease

Pediatric Anesthesia

For Peer Review

1

Intraoperative changes in blood pressure associated with cerebral desaturation in

infants

Running title: Intraoperative hypotension in infants

Daphné MICHELET 1,4

, Ozkan ARSLAN 1,4

, Julie HILLY 1,4

, Nyamjargal MANGALSUREN

1,4, Christopher BRASHER

1 4, Robert GRACE

2, Arnaud BONNARD

3,4, Serge MALBEZIN

1,4, Yves NIVOCHE

1,4, Souhayl DAHMANI

1,2,4,5.

1 Department of Anesthesia, Intensive Care and Pain Management, AP-HP, Robert Debré

University Hospital. Paris, France.

2 Department of Anesthesia, Intensive Care and Peri-operative Medicine, Cairns Hospital,

Queensland, Australia

3 Department of General and Urological Surgery, AP-HP, Robert Debré University Hospital.

Paris Diderot University. Paris, France.

4 Paris Diderot University (Paris VII). Pres Paris Sorbonne Cité. Paris, France.

5 University and Hospital Department PROTECT. Robert Debré University Hospital. Paris,

France.

Corresponding author: Professor Souhayl Dahmani, MD, PhD. Department of Anesthesia,

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Intensive Care and Pain Management. Robert Debré Hospital, 48 Bd Sérurier, 75019 Paris,

France

Phone: + 33 1 40 03 41 83

Fax: + 33 1 40 03 20 00

E-mail: souhayl.dahmani@rdb.aphp.fr

Keywords: hypotension, infants, newborn, cerebral oxygenation

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What is already known: Pediatric hypotension has been defined as a decrease in mean

blood pressure of 20-30% from baseline. However there is little evidence to support this

definition.

During non-cardiac surgery in neonates and infants less than 3 months, decreases in

systolic blood pressure of less than 20% from baseline are associated with a <10%

chance of cerebral desaturation. Falls in systolic arterial pressure > 20 % must be

avoided in infants under 3 months.

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Abstract

Background: Intraoperative hypotension has been linked to poor postoperative neurological

outcomes. However, the definition of hypotension remains controversial in children. We

sought to determine arterial blood pressure threshold values associated with cerebral

desaturation in infants.

Methods: After ethical committee approval, infants younger than 3 months were included in

this prospective observational study. Cerebral saturation was assessed using near-infrared

spectroscopy. The primary goal of the study was to determine percentage reductions in

intraoperative SBP and MBP associated with decreases in cerebral blood oxygen saturation of

greater than 20%, when compared to baseline. Analyses were performed using a bootstrap

receiving operator characteristics (ROC) curves with determination of the grey zone.

Results: Sixty patients were recruited and 960 measurement points recorded. 59 data points

(6.1%) recorded cerebral desaturation of greater than 20% when compared to baseline. The

areas under the ROC curves were 0.79 [0.74 - 0.84] and 0.67 [0.6 – 0.75] for percentage

decreases in SBP and MBP, respectively. Grey zone values with false positive and negative

rates less than 10% were SBP decreases of 20.5% and 37.5% respectively, and MBP

decreases of 15.5% and 44.5% respectively.

Discussion: Our results indicate that falls in non-invasive systolic blood pressure of <20%

from baseline are associated with a <10% chance of cerebral desaturation in neonates and

infants less than 3 months of age undergoing non-cardiac surgery. As such, maintaining

systolic blood pressure above this threshold value appears a valid clinical target.

Word count: 236

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Introduction

Intraoperative hypotension is widely considered to be a risk factor for poor cardiac and

neurological outcome following cardiac and non-cardiac surgery in adults and in children (1-

5). As a result anesthesiologists are focused on the prevention of intraoperative hypotension.

Pediatric hypotension has been defined as a systolic blood pressure below 60 mmHg

(Advanced Pediatric Life Support) or a decrease in mean blood pressure of 20-30% from

baseline (6-8). However there is little evidence to support these definitions.

The development of near-infrared spectroscopy (NIRS) technology allows for cerebral

tissue oxygenation measurement (StcO2) (9-11). NIRS measures cerebral hemoglobin

saturation transcranially at depths of 1 to 1.5 cm. Given that 70% of intracranial blood is

venous, it predominantly reflects venous hemoglobin oxygen saturation, which is influenced

by arterial saturation, oxygen consumption, blood flow and plasma hemoglobin levels.

Consequently, common clinical mechanisms of cerebral desaturation include (a) hypotension

and decrease of cerebral blood flow (b) arterial desaturation, (c) increased cerebral metabolic

rate, (d) vasoconstriction due to exogenous or endogenous catecholamines, (e) changes in

CO2 partial pressure, and (f) reduced plasma hemoglobin levels.

Several authors have described an association between reduced cerebral tissue oxygenation

and poor neurological outcome during cardiac surgery and neuro-trauma (12-16). This study

aimed to determine if a relationship exists between intra-operative non-invasive blood

pressure (NIBP) measurements and NIRS measurement of cerebral tissue oxygenation. The

objective is to provide clinically relevant values for blood pressure management in infants less

than 3 months of age to minimize the risk of intra-operative cerebral deoxygenation and poor

neurological outcomes post-surgery (17).

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Material and Methods

This is an observational study approved by the IRB (Comité d’Evaluation de l’Ethique des

projets de Recherche Biomédicale (CEERB) de Robert Debré; # 12-021) and the French

National Data Protection Committee. Written informed consent was obtained from all

patients’ parents.

Inclusion/Exclusion criteria

Patients aged ≤ 3 months; ASA status 1 – 3, undergoing surgery and requiring general

anesthesia were eligible for enrolment. Patients with known neurological or cardiac

conditions were excluded, including patent ductus arteriosus, as were patients whose

procedures required laparoscopy or the prone position. Patients receiving preoperative or

intraoperative sympathomimetic drugs were excluded (except for atropine when used for

reversal of muscle relaxation at the end of surgery). If peripheral oxygen saturations were less

than 95% the associated data points were excluded due to the potential impact on StcO2

measurements.

Intraoperative anesthesia management

Patients were not premedicated and were fasted as per local protocols. Monitoring

included heart rate (HR), non-invasive blood pressure monitoring (NIBP) (CARESCAPE

MONITOR B650, General Electrics Healthcare, Fairfield, CT 06828, USA) with the cuff on

the upper arm, peripheral arterial oxygen saturation (SaO2) measured on the right hand; end

tidal CO2 (ETCO2), gas monitoring (sevoflurane and O2), spirometry (gas flows, volumes and

pressures) and temperature via a rectal or esophageal probe. All patients received three

minutes preoxygenation. The majority of patients (56/60 [93%]) were patients considered at

risk of aspiration, and received rapid sequence inductions using propofol (5 to 7 mg.kg

-1) and

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suxamethonium (1.5 mg.kg

-1) followed by sufentanil (0.2 µg

.kg

-1) and atracurium (0.5 mg

.kg

-

1) after intubation. Four patients received gas inductions using sevoflurane (6% in a 50%

O2/air mix), followed by sufentanil (0.2 µg.kg

-1) and atracurium (0.5 mg

.kg

-1) prior to oro-

tracheal intubation. For all patients, anesthesia was maintained with sevoflurane at 1.5 to 3%

end tidal expired concentration in a 50% O2/air mix. Patients were pressure ventilated using a

circle circuit, without positive end-expiratory pressure. Target EtCO2 pressure was 35-39

mmHg and target peak airway pressure 10-18 cmH2O. Additional intraoperative analgesia

was provided with sufentanil boluses of 0.1 µg.kg

-1 when heart rate (HR) or mean blood

pressure (MBP) increased by 20% on preoperative values. Muscle relaxation was reversed at

the end of surgery using neostigmine (40 µg.kg

-1) and atropine (20 µg

.kg

-1). Patients were

actively warmed with forced air warmers.

Intraoperative fluid and blood pressure management

Intraoperative crystalloids (Ringer’s lactate with 1% glucose - Polyionique B66

solution, Paris Hospitals Group) were administered according to the Holliday and Segar

formulae with compensation for preoperative fasting and predicted surgical fluid losses. All

further filling was performed with boluses of 0.9% normal saline. All patients received a 10

ml.kg

-1 loading bolus over 15 minutes before induction. Additional 10 ml

.kg

-1 normal saline

boluses were administered intraoperatively at the anesthesiologist’s discretion according to

blood pressure, ETCO2, urine output, HR changes or during long duration or high fluid loss

surgery. According to our institutional protocol, anesthesiologists also administered 10 ml.kg

-

1 normal saline boluses where a decrease in StcO2 occurred of more than 20% when

compared to preoperative values. If this bolus did not result in < 20% reduced StcO2 values

when compared to preoperative values (or the correction of the trigger element), a second

bolus was administered and the expiratory concentration of sevoflurane was decreased.

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Data collection

Demographic and surgical data were recorded: age, weight, operation type and

duration. Measurements were not blinded and data were collected during surgery. All values

were measured twice in order to reduce regression to the mean. The following intraoperative

parameters were recorded every 10 minutes: HR, non-invasive systolic blood pressure (SBP),

diastolic blood pressure (DBP), mean blood pressure (MBP), arterial saturation (SaO2), end-

tidal carbon dioxide (ETCO2 : sidestream sampling of expired circuit gas analysis without

arterial blood gas confirmation), cerebral oxygen saturation (StcO2: INVOS, Covidien,

Levallois-Perret. France) with the probe placed in the lateral frontal region, end tidal

sevoflurane concentration and patient core temperature. StcO2 was continuously monitored

over and above data recording every 10 minutes. The 10 minutes interval was based on our

current practice as the study was an observational study.

Statistical analysis

The primary goal of this study was to determine what reductions in arterial pressure

(SBP and MBP) were associated with a decrease in StcO2 (∆StcO2) of greater than 20%

lasting at least one minute. StcO2 was continuously monitored and data recorded every 10

minutes. One minute reductions of 20% in StcO2 have been judged clinically relevant in other

studies and proposed as a target for initiating corrections measures associated with an

improvement in postoperative outcome (18, 19). Blood pressure analyses were performed

according to absolute numeric values and to percentage changes from baseline (before

induction of anesthesia). Receiving operator characteristics (ROC) curve analyses were

performed with determination of the area under the curve (AUC), sensitivity, specificity and

95% confidence intervals for both SBP and MBP. Using the grey zone method, optimal SBP

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and MBP values were determined to predict ∆StcO2 > 20% (20). This methodology

determines the ranges of explored values that minimize the risk of misclassifying cerebral

desaturation episodes (false negatives: the result of absence of cerebral desaturation when

cerebral desaturation is present) and absence of cerebral desaturation (false positives: the

result of cerebral desaturation when cerebral desaturation is not present) for the studied

outcome with a tolerance of 10% (sensitivity and specificity equal or more than 0.9). The 90%

probability chosen in this study was based on potential blood pressure measurement errors

and regional cerebral differences in StcO2 that average 10% (20-23). Grey zone thresholds

were defined using receiver operating characteristic (ROC) curve analysis and determination

of the maximal Youden’s J statistic (sensitivity + specificity). The grey zone approach allows

for the determination of values that define errors and are of direct clinical application. ROC

analyses were performed using a 1,000 time bootstrap method allowing for re-sampling of

original data in order to increase statistical precision. The repeated measurement was not

taken in account in the computation of ROC analyses.

The data are presented as mean ± standard deviation where sample sizes are ≥ 30, and

median [minimum-maximum] where sample sizes <30. Given clinical interventions upon

StcO2, the normality of the distribution of this parameter was checked using the Shapiro-

Wilks test. AUC, sensitivity and specificity are expressed as median [95 % confidence

interval]. Grey zone limits are expressed as [low limit – high limit] and only considered when

the 95% confidence intervals for sensitivity and specificity include 0.9. Discrete variables are

expressed as numbers (percentages) and are compared using the Chi² test or Fisher’s exact

test. Continuous variable data are considered as normally distributed when sample sizes

exceed 30 and were compared using analysis of variance (ANOVA) or analysis of covariance

(ANCOVA) taking into account repeated measures in each patient. This statistical

methodology allows for the effects of repeated measurement on the differences between

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groups. Otherwise, a Mann and Whitney test was performed for samples of less than 30. The

null hypothesis was rejected for p values less than 0.05. All these statistics were performed on

the overall population and in the subgroups of preterm and full term infants. Statistical

analyses were performed using SPSS 20.0 software (IBM Company, Chicago, Illinois, USA)

and the R software 3.0.1 for ROC analyses (The R Foundation for Statistical Computing,

Vienna, Austria).

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Results:

Sixty patients were recruited over a 6 month period. The population description and

baseline study values are displayed in table 1. Sixteen patients (26%) were preterm infants

born at < 37 weeks postmenstrual age. Surgical procedures included: 46 cases of emergency

abdominal or thoracic surgery, 7 central venous catheter insertions, 4 urological procedures, 1

imperforate hymen, 1 pharyngeal teratoma and 1 endoscopy.

Pre-anesthetic reference values for SBP, MBP, DBP and StcO2 are displayed in table 1. StcO2

exhibited normal distribution according to the Shapiro-Wilks test. There was no significant

difference in values between preterm and term infants. A total of 960 measurement points

were recorded. Three measurement points were discarded because of peripheral SaO2

readings less than 95%. 59 data points (6.1%) recorded a ∆StcO2 of greater than 20%. These

involved 18 events in 4 premature infants and 41 events in 10 term infants. Sevoflurane was

used as an induction agent in only 4 patients (29 data points), none of them exhibited cerebral

desaturation (∆StcO2 of greater than 20%) during induction. All other patients received

intravenous propofol anesthetic inductions. Sixteen correction interventions were performed

according to StcO2: 8 required a single bolus of 10 ml.kg

-1 of normal saline before correction

and 7 required two boluses and one both two normal saline boluses and the decrease of

expiratory sevoflurane. When data points with and without cerebral desaturation were

compared the following parameters differed significantly: absolute SBP and MBP values, the

percentage decrease of SBP, MBP, DBP when compared to baseline, and HR. This difference

was significant using both ANOVA and ANCOVA analysis (table 2).

The area under the receiver operator curve (AUROC) for absolute SBP (0.64 [0.55 –

0.71], p < 0.001) and MBP (0.62 [0.54 – 0.7], p < 0.001) were significantly different from the

line of identity for predicting of ∆StcO2 > 20%. As the AUROC for absolute values of SBP

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and MBP were of poor clinical value, and given that blood pressure values vary with age and

prematurity status (20), grey zone analyses were performed only for relative changes in blood

pressure. The percentage decrease in SBP and MBP when compared to baseline values

exhibited significant results (figures 1A, 1B). Areas under the ROC curves were higher: 0.79

[0.74 - 0.84] (p = 0.0001) and 0.67 [0.6 – 0.75] (p < 0.001), for the percentage decrease of

SBP and MBP, respectively (Table 3). Grey zone values with false positive rates less than

10% and false negative rates less than 10%, were 20.5% and 37.5% reductions in SBP and

15.5% and 44.5% reductions in MBP (Table 3). The J point for percentage reduction in SBP

was 28.5% with sensitivity at this point of 0.7 [0.6 - 0.8] and specificity 0.75 [0.72 - 0.77].

The J point for reduction in MBP was 40.5 % with sensitivity of 0.4 [0.33 – 0.59] and

specificity 0.83 [0.81 – 0.86] (Table 3). The same analyses were performed for term and

preterm patients (Table 4). No differences were found in AUROC or J-point values. However,

grey zone values differed; much larger decreases of SBP and MBP were required in

premature infants to achieve a false negative rate less than 10%. This study is not powered or

designed to statistically test this observed difference any further.

Further analyses of data points involving cerebral desaturation were then performed. There

was no significant difference in chronological age or postmenstrual age between those who

desaturated and those who did not (table 5). There was also no significant difference in SBP,

MBP or percentage decrease in MBP between preterm and full term patients during cerebral

desaturation (Table 5). The percentage decrease in SBP was significantly greater in preterm

patients while both HR and temperature were significantly lower in preterm patients (Table

5). Heart rate was negatively correlated with the percentage fall in SBP in premature patients

(r = -0.4, p < 0.0001).

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Discussion

The key findings of this study are: a decrease of SBP less than 20.5%, or MBP less

than 15.5%, during surgery in neonates and infants < 3 months of age predicted a probability

of cerebral desaturation (defined as ∆StcO2 > 20%) of less than 10%. A decrease of SBP

more than 37.5% and MBP more than 44.5% predicted a probability of cerebral desaturation

greater than 90%. Based on these results avoiding a fall in SBP of more than ~20% and a fall

in MBP of more than ~15 % are acceptable targets to avoid cerebral desaturation.

The effect of intraoperative hypotension on brain oxygenation is difficult to assess

using standard monitoring (6). Auto-regulation maintains cerebral perfusion and oxygenation

to a variable degree, and cerebral oxygen demand may also vary (11, 12, 24). Cerebral auto-

regulation and oxygen demand are affected by age, prematurity, and co-existing medical

conditions (25-27). A recent retrospective study by McCann et al (5) described several cases

of postoperative encephalopathy following low non-invasive arterial blood pressure

measurements. However, such findings have been contested in neonates (28). Our results do

support the Society of Pediatric Anesthesia definition of the limits of acceptable reductions in

SBP as a decrease of 20 - 30% from baseline7. Interestingly, normal sleep in neonates and

infants has also been associated with a decrease in blood pressure of 6 to 10% (29). Moreover,

depending on sleep position and prematurity status, this decrease has been associated with

impairment in baroreflex activity, blood pressure and heart rate adaptation (29-31). NIRS is

relatively new technology allowing real-time cerebral oxygen saturation monitoring. Cerebral

oxygen saturation is dependent upon arterial saturation, blood pressure, hemoglobin levels,

cerebral metabolic rate and CO2 partial pressure. Given a stable hemoglobin levels, a stable

CO2 partial pressure, and the exclusion of data coinciding with arterial desaturation, NIRS

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should reflect the net effect of cardiac output and blood pressure upon cerebral saturation (10,

18). Over the last decade many studies have employed these devices for patient monitoring

and indirect assessment of cerebral blood flow auto-regulation (12, 18). Recently ∆StcO2 was

found to be predictive of poor neurological outcome following cardiac surgery and in the

neonatal intensive care unit (11, 12). That said, NIRS is not yet routine monitoring: standard

patient care chiefly depends on arterial blood pressure monitoring as an indirect measure of

cerebral perfusion (10). As such, defining what is an acceptable reduction in arterial pressure

during surgery is an important issue, particularly so during infant and neonatal surgery where

normal values are less well defined. However, “normal” blood pressure values are

controversial and originate from consensus rather than evidence (7). For these reasons NIRS

was used in our study to estimate the clinical limits of arterial blood pressure to avoid cerebral

desaturation.

As described in other studies and as is common in daily practice, blood pressure was

measured non-invasively. Rhondali et al (32) recently assessed cerebral blood flow using

transcranial Doppler and found cerebral blood flow was reduced when MBP, measured non-

invasively, decreased by >20%, compared to preoperative values. The same authors also

determined absolute and relative MBP values associated with impaired cerebral oxygenation

during induction with sevoflurane (33). They found that no cerebral desaturation occurred

with 37% decreases in MAP (sensitivity 75 [95% confidence interval: 68-82] and specificity

76 [95% confidence interval: 52-91]). These are similar results to our findings. However, our

study differs to Rhondali et al. in two significant ways. Firstly, it analyses data throughout the

operative period, not just after induction of anesthesia, and secondly, most patients were given

propofol as an induction agent, potentially favoring the occurrence of hypotension.

Interestingly, AUROC analysis for percentage reduction in MBP produced less pertinent

values than analysis for SBP, and AUC values for numeric reductions in MBP are less

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significant, contradicting other studies.

Cerebral desaturation was associated with larger decreases in blood pressure in

premature infants, when compared with term infants. This might involve impaired pressure

regulation previously described in this population (7, 34) predisposing them to more profound

hypotension in response to anesthesia (8). Unfortunately, our data and study power are

insufficient to draw conclusions in this sub-group with the small number of cerebral

desaturation events occurring in preterm patients leading to sampling error. Further studies are

required on the limits of blood pressure associated with cerebral desaturation in this

population.

HR was significantly lower in preterm infants when delta StcO2 was greater than 20%.

Lower HR may have contributed to the decrease in StcO2 given that cardiac output is HR-

dependent in preterm infants (especially before 30 gestational age) (35, 36). In addition,

Lower HR in preterm infants with cerebral desaturation was associated with a greater

reduction in SBP than that observed in the term subjects with cerebral desaturation. None of

the study subjects had a gestational age less than 30 weeks.

Cerebral saturation, as measured by NIRS depends upon partial pressure of CO2. Importantly

there was no difference in ETCO2 observed between points with or without cerebral

desaturation. However, ETCO2 measurement is less accurate in small children, and

increasingly so increasing respiratory rate. In addition, no arterial blood gas analyses were

performed (because this was an observational study) to confirm ETCO2 values. Finally,

expired sevoflurane concentrations were within ranges compatible with preserved auto-

regulation (i.e. 0.8 and 1.5 MAC) (37) and did not differ between measurement points with

and without cerebral desaturation.

This study, like all studies, has limitations. Blood pressure was monitored non-

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invasively (21). Although not the gold standard this reflects common day to day practice. The

number of cerebral desaturation events is low and occurred in a limited number of patients,

and just 4 preterm patients. Hopefully further studies will specifically focus on blood pressure

and cerebral saturation in preterm patients. Another important limitation of our study was the

10 minutes interval for collecting data. This might have induced missed desaturation values.

AUROC values are low, especially for reductions in MBP. However grey zone statistical

analysis limited the impact of these weak results as only values with an error risk below 10 %

were considered for further interpretation. Although NIRS has been shown to strongly

correlate with Jugular Bulb oxygen saturation (SjO2) over a wide range of normal and

abnormal values, recent studies have emphasized the effects of exogenous catecholamine on

StcO2 (16, 27). Operative pain and stress may induce endogenous catecholamine secretion

that may potentially modify StcO2 interpretation. StcO2 monitoring was performed in the

frontal cerebral region in all patients, and as such, regional differences in blood flow and

metabolism could not be detected (23). In particular, cerebral desaturation that occurs in

periventricular white matter in preterm patients may be undetectable, leading to an

underestimation in cerebral desaturation frequency (23, 38). Finally, our threshold defining

significant cerebral desaturation (-20%) was based on previous studies performed in intensive

care and during cardiac surgery. Currently, no study has investigated the threshold of cerebral

desaturation associated with long term neurological outcomes in children during non-cardiac

surgery.

In conclusion, during non-cardiac surgery in neonates and infants less than 3 months,

falls in systolic blood pressure of < 20% from baseline are associated with a <10% chance of

cerebral desaturation defined as a decrease of cerebral saturation > 20 %. As such,

maintaining systolic blood pressure within 20% of baseline values appears a valid clinical

target. Future studies focusing specifically on preterm patients will be useful.

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Funding: this study was funded by institutional resources.

Financial Disclosure Statement: no for all authors

Conflict of interest: no for all authors.

References

1. Bijker JB, Gelb AW. Review article: the role of hypotension in perioperative stroke.

Can J Anaesth 2013; 60: 159-67

2. Bijker JB, Persoon S, Peelen LM, et al. Intraoperative hypotension and perioperative

ischemic stroke after general surgery: a nested case-control study. Anesthesiology

2012; 116: 658-64

3. Walsh M, Devereaux PJ, Garg AX, et al. Relationship between intraoperative mean

arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical

definition of hypotension. Anesthesiology 2013; 119: 507-15

4. Botto F, Alonso-Coello P, Chan MT, et al. Myocardial injury after noncardiac surgery:

a large, international, prospective cohort study establishing diagnostic criteria,

characteristics, predictors, and 30-day outcomes. Anesthesiology 2014; 120: 564-78

5. McCann ME, Schouten AN, Dobija N, et al. Infantile postoperative encephalopathy:

perioperative factors as a cause for concern. Pediatrics 2014; 133: e751-7

6. Nafiu OO, Voepel-Lewis T, Morris M, et al. How do pediatric anesthesiologists define

intraoperative hypotension? Paediatr Anaesth 2009; 19: 1048-53

7. Vutskits L. Cerebral blood flow in the neonate. Paediatr Anaesth 2014; 24: 22-9

8. Wolf AR, Humphry AT. Limitations and vulnerabilities of the neonatal cardiovascular

system: considerations for anesthetic management. Paediatr Anaesth 2014; 24: 5-9

9. Brady KM, Lee JK, Kibler KK, et al. Continuous time-domain analysis of

cerebrovascular autoregulation using near-infrared spectroscopy. Stroke 2007; 38:

2818-25

10. Kasman N, Brady K. Cerebral oximetry for pediatric anesthesia: why do intelligent

clinicians disagree? Paediatr Anaesth 2011; 21: 473-8

11. Hayashida M, Kin N, Tomioka T, et al. Cerebral ischaemia during cardiac surgery in

children detected by combined monitoring of BIS and near-infrared spectroscopy. Br J

Anaesth 2004; 92: 662-9

12. Brady KM, Mytar JO, Lee JK, et al. Monitoring cerebral blood flow pressure

autoregulation in pediatric patients during cardiac surgery. Stroke; a Journal of

Cerebral Circulation 2010; 41: 1957-62

13. Chiaretti A, Piastra M, Pulitanò S, et al. Prognostic factors and outcome of children

with severe head injury: an 8-year experience. Childs Nerv Syst 2002; 18: 129-36

14. Hoffman GM, Brosig CL, Mussatto KA, Tweddell JS, Ghanayem NS. Perioperative

cerebral oxygen saturation in neonates with hypoplastic left heart syndrome and

childhood neurodevelopmental outcome. J Thorac Cardiovasc Surg 2013; 146: 1153-

64

15. Kussman BD, Wypij D, Laussen PC, et al. Relationship of intraoperative cerebral

oxygen saturation to neurodevelopmental outcome and brain magnetic resonance

imaging at 1 year of age in infants undergoing biventricular repair. Circulation 2010;

122: 245-54

Page 17 of 25 Pediatric Anesthesia

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18

16. Neshat Vahid S, Panisello JM. The state of affairs of neurologic monitoring by near-

infrared spectroscopy in pediatric cardiac critical care. Curr Opin Pediatr 2014; 26:

299-303

17. Kussman BD, Wypij D, DiNardo JA, et al. Cerebral oximetry during infant cardiac

surgery: evaluation and relationship to early postoperative outcome. Anesth Analg

2009; 108: 1122-31

18. Murkin JM, Arango M. Near-infrared spectroscopy as an index of brain and tissue

oxygenation. Br J Anaesth 2009; 103 Suppl 1: i3-13

19. Austin EH, 3rd, Edmonds HL, Jr., Auden SM, et al. Benefit of neurophysiologic

monitoring for pediatric cardiac surgery. J Thorac Cardiovasc Surg 1997; 114: 707-

15, 17; discussion 15-6

20. Coste J, Pouchot J. A grey zone for quantitative diagnostic and screening tests. Int J

Epidemiol 2003; 32: 304-13

21. Konig K, Casalaz DM, Burke EJ, Watkins A. Accuracy of non-invasive blood

pressure monitoring in very preterm infants. Intensive Care Med 2012; 38: 670-6

22. Sorensen H, Secher NH, Siebenmann C, et al. Cutaneous vasoconstriction affects

near-infrared spectroscopy determined cerebral oxygen saturation during

administration of norepinephrine. Anesthesiology 2012; 117: 263-70

23. McClure MM, Riddle A, Manese M, et al. Cerebral blood flow heterogeneity in

preterm sheep: lack of physiologic support for vascular boundary zones in fetal

cerebral white matter. J Cereb Blood Flow Metab 2008; 28: 995-1008

24. Han SH, Bahk JH, Kim JH, et al. The effect of esmolol-induced controlled

hypotension in combination with acute normovolemic hemodilution on cerebral

oxygenation. Acta Anaesthesiol Scand 2006; 50: 863-8

25. Fuchs H, Lindner W, Buschko A, Trischberger T, Schmid M, Hummler HD. Cerebral

oxygenation in very low birth weight infants supported with sustained lung inflations

after birth. Pediatr Res 2011; 70: 176-80

26. Fuchs H, Lindner W, Buschko A, Almazam M, Hummler HD, Schmid MB. Brain

oxygenation monitoring during neonatal resuscitation of very low birth weight infants.

J Perinatol 2012; 32: 356-62

27. Hahn GH, Heiring C, Pryds O, Greisen G. Cerebral vascular effects of hypovolemia

and dopamine infusions: a study in newborn piglets. Acta Paediatr 2012; 101: 736-42

28. Alderliesten T, Lemmers PM, van Haastert IC, et al. Hypotension in preterm neonates:

low blood pressure alone does not affect neurodevelopmental outcome. J Pediatr

2014; 164: 986-91

29. de Swiet M, Fayers P, Shinebourne EA. Systolic blood pressure in a population of

infants in the first year of life: the Brompton study. Pediatrics 1980; 65: 1028-35

30. Witcombe NB, Yiallourou SR, Walker AM, Horne RS. Blood pressure and heart rate

patterns during sleep are altered in preterm-born infants: implications for sudden

infant death syndrome. Pediatrics 2008; 122: e1242-8

31. Witcombe NB, Yiallourou SR, Sands SA, Walker AM, Horne RS. Preterm birth alters

the maturation of baroreflex sensitivity in sleeping infants. Pediatrics 2012; 129: e89-

96

32. Rhondali O, Mahr A, Simonin-Lansiaux S, et al. Impact of sevoflurane anesthesia on

cerebral blood flow in children younger than 2 years. Paediatr Anaesth 2013; 23: 946-

51

33. Rhondali O, Juhel S, Mathews S, et al. Impact of sevoflurane anesthesia on brain

oxygenation in children younger than 2 years. Paediatr Anaesth 2014; 24: 734-40

34. Wong FY, Leung TS, Austin T, et al. Impaired autoregulation in preterm infants

identified by using spatially resolved spectroscopy. Pediatrics 2008; 121: e604-11

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35. Rhee CJ, Fraser CD, 3rd, Kibler K, et al. The ontogeny of cerebrovascular pressure

autoregulation in premature infants. J Perinatol 2014; 34: 926-31

36. Mitra S, Czosnyka M, Smielewski P, O'Reilly H, Brady K, Austin T. Heart rate

passivity of cerebral tissue oxygenation is associated with predictors of poor outcome

in preterm infants. Acta Paediatr 2014; 103: e374-82

37. Wong GT, Luginbuehl I, Karsli C, Bissonnette B. The effect of sevoflurane on

cerebral autoregulation in young children as assessed by the transient hyperemic

response. Anesth Analg 2006; 102: 1051-5

38. Volpe JJ. Neurobiology of periventricular leukomalacia in the premature infant.

Pediatr Res 2001; 50: 553-62

Figure caption

Figure 1: Receiving operator characteristics (ROC) analyses for the relation between percent

decrease of systolic (A) and mean (B) blood pressure, and cerebral oxygen desaturation in the

overall data points.

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Table 1: Population data, expressed as mean ± sd or N (%).

Parameters Values

Baseline SBP (mm Hg) 87 ± 16

Baseline MBP (mm Hg) 64 ± 13

Baseline DBP (mm Hg) 48 ± 12

StcO2 (%) 78 ± 10

Age (days) 22 ± 22

Gestational age at birth (weeks) 37 ± 4

Postconceptual age (weeks) 40 ± 4

Propofol induction (N (%)) 56 (93%)

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Table 2: Comparison between data points with cerebral oxygen desaturation (∆Stc02 > 20 %)

and absence of cerebral oxygen desaturation (∆Stc02 ≤ 20 %). p denotes non-adjusted

comparison, P (covariance) denotes comparison with repeated measures as covariance.

Abbreviations: StcO2: cerebral oxygen saturation, HR: heart rate, SaO2: arterial oxygen

saturation, ETCO2: end-tidal expired CO2, FiO2: inspired fraction of oxygen.

Factor ∆Stc02 ≤ 20 % ∆Stc02 > 20 % p P (covariance)

Systolic blood pressure (SBP) mmHg 71 ± 15 62 ± 15 0.001 < 0.0001

Mean blood pressure (MBP) mmHg 49 ± 13 43 ± 13 0.004 0.001

Diastolic blood pressure (DBP) mmHg 35 ± 11 32 ± 12 0.08 0.02

StcO2 (%) 78 ± 12 56 ± 9 < 0.0001 < 0.0001

Percentage decrease in SBP 17 ± 18 34 ± 12 < 0.0001 < 0.0001

Percentage decrease in MBP 19 ± 26 35 ± 23 < 0.0001 < 0.0001

Percentage decrease in DBP 20 ± 34 36 ± 26 0.002 < 0.0001

HR (bpm) 140 ± 20 132 ± 16 0.04 0.02

SaO2 (%) 99 ± 1 99 ± 1 0.12 0.43

ETCO2 (mmHg) 37 ± 1.7 37 ± 1.9 0.44 0.3

FiO2 (%) 51 ± 7.5 50 ± 0.1 0.28 0.28

% Expired Sevoflurane 2 ± 1.7 2 ± 0.7 0.6 0.97

Temperature (Celsius Degrees) 36 ± 1.5 36 ± 0.8 0.36 0.2

Preterm (%) 25 % 22.7 % 0.55 -

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Table 3: Receiving operator characteristics (ROC) analyses for the relation between

percentage decrease in systolic blood pressure and cerebral oxygen desaturation in all

patients, term and preterm patients. Determination of the area under the curve (AUC), J point,

sensitivity at J point, specificity at J point and interval of the grey zone. Results are expressed

as thresholds (J point and grey zone) or media [95 % confidence interval].

AUC J point Se J Sp J Grey zone

All patients 0.79 [0.74 - 0.84] 28.5 % 0.7 [0.6 - 0.8] 0.75 [0.72 - 0.77] 20.5 % - 37.5 %

Preterm 0.84 [0.77-0.88] 31.5 % 0.74 [ 0.6 – 0.8] 0.74 [ 0.7 - 0.78] 32.5 % - 39.5 %

Term 0.76 [0.7 – 0.83] 28.5 % 0.63 [0.57 - 0.80] 0.7 [0.77 – 0.8] 20.5 % - 36.5 %

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Table 4: Receiving operator characteristics (ROC) analyses for the relation between

percentage decrease in mean blood pressure and cerebral oxygen desaturation in all patients,

term and preterm patients. Determination of the area under the curve (AUC), J point,

sensitivity at J point, specificity at J point and interval of the grey zone. Results are expressed

as thresholds (J point and grey zone) or media [95 % confidence interval].

AUC J point Se J Sp J Grey zone

All patients 0.67 [0.6 – 0.75] 40.5 % 0.4 [0.33 – 0.59] 0.83 [0.81 – 0.86] 15.5 % - 44.5 %

Preterm 0.72 [0.6-0.83] 40.5 % 0.5 [ 0.3 - 0.7] 0.8 [0.74 - 0.85] 30.5 % - 47.5 %

Term 0.65 [0.55 -0.75] 42.5 % 0.4 [0.3 - 0.6] 0.87 [0.85 - 0.9] 13.5 % - 42.5 %

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Table 5: Comparison between term and preterm patients with cerebral desaturation.

Abbreviations: SBP: systolic blood pressure, MBP: mean blood pressure, DBP: diastolic

blood pressure. HR: heart rate, SaO2: arterial oxygen saturation, ETCO2: end-tidal expired

CO2, FiO2: inspired fraction of oxygen.

Parameter Term Preterm p value

Chronological Age (days) 5 [1 - 86] 28 [5 - 74] 0.29

Age at birth (weeks) 39 [37 - 41] 35 [26 - 36] 0.004

Postmenstrual age (weeks) 41 [37 - 50] 39 [30 - 40] 0.06

SBP (mmHg) 62 [34 - 93] 62 [38 - 75] 0.73

MBP (mmHg) 45 [23 - 75] 43 [20 - 52] 0.55

DBP (mmHg) 32 [15 - 75] 25[ 15 - 44] 0.2

Percent decrease SBP 31 [3 - 56] 39 [19 - 66] 0.04

Percent decrease MBP 28 [-9 - 67] 37 [13 - 76] 0.2

Percent decrease DBP 29 [-40 - 77] 45 [17 - 65] 0.06

HR (bpm) 140 [85 - 160] 120 [101 - 140] < 0.0001

SaO2 (%) 98.5 [95 - 100] 99 [98 - 100] 0.22

ETCO2 (mmHg) 36 [34 - 44] 36 [36 - 39] 0.26

FiO2 (%) 50 50 1

% Expired Sevoflurane 2.3 [1.5 - 3] 2 [1.3 - 2.7] 0.09

Temperature (Celsius, degrees) 36.6 [35 – 37.3] 36 [34.5 – 36.8] 0.01

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190x254mm (96 x 96 DPI)

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