Dynamic optic nerve sheath diameter changes upon moderate hyperventilation in patients with traumatic brain injury

Journal Pre-proof Dynamic optic nerve sheath diameter changes upon moderate hyperventilation in patients with traumatic brain injury

Stephanie Klinzing, Matthias Hilty, Ursina Bechtel-Grosch, Reto Andreas Schuepbach, Philipp Bühler, Giovanna Brandi PII:

S0883-9441(19)31856-8

DOI:

https://doi.org/10.1016/j.jcrc.2020.01.008

Reference:

YJCRC 53466

To appear in:

Journal of Critical Care

Please cite this article as: S. Klinzing, M. Hilty, U. Bechtel-Grosch, et al., Dynamic optic nerve sheath diameter changes upon moderate hyperventilation in patients with traumatic brain injury, Journal of Critical Care(2019), https://doi.org/10.1016/j.jcrc.2020.01.008

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

© 2019 Published by Elsevier.

Journal Pre-proof Dynamic optic nerve sheath diameter changes upon moderate hyperventilation in patients with traumatic brain injury Stephanie Klinzing, Matthias Hilty, Ursina Bechtel-Grosch, Reto Andreas Schuepbach, Philipp Bühler, Giovanna Brandi

Stephanie Klinzing, MD Institute for Intensive Care Medicine, University Hospital of Zurich, Switzerland [email protected] Matthias P Hilty, MD Institute for Intensive Care Medicine, University Hospital of Zurich, Switzerland [email protected]

ro

of

Ursina Bechtel-Grosch, MD Institute for Intensive Care Medicine, University Hospital of Zurich, Switzerland [email protected]

-p

Philipp Bühler, MD Institute for Intensive Care Medicine, University Hospital of Zurich, Switzerland [email protected]

re

Reto Andreas Schüpbach, MD Institute for Intensive Care Medicine, University Hospital of Zurich, Switzerland [email protected]

na

lP

Giovanna Brandi, MD Institute for Intensive Care Medicine, University Hospital of Zurich, Switzerland [email protected]

Jo ur

Corresponding author: Stephanie Klinzing, MD

Institute for Intensive Care Medicine, University Hospital of Zurich, Rämistrasse 100, 8091, Zurich, Switzerland Tel: +41 44 255 23 76

Fax: +41 44 255 31 72

Declarations of interest: none

Journal Pre-proof

Abstract Background Sonographic assessment of optical nerve sheath diameter (ONSD) has the potential for non-invasive monitoring of intracranial pressure (ICP). Hyperventilation (HV) -induced hypocapnia is used in the management of patients with traumatic brain injury (TBI) to reduce ICP. This study investigates, whether sonography is a reliable tool to detect dynamic changes in ONSD.

of

Methods

ro

This prospective single center trial included patients with TBI and neuromonitoring within 36 hours after injury. Data collection and ONSD measurements were performed at baseline and during moderate HV for 50 minutes.

-p

Patients not suffering from TBI were recruited as control group.

re

Results

lP

Ten patients with TBI (70% males, mean age 35 ± 14 years) with a median of first GCS of 5.9 and ten control patients (40% males, mean age 45 ± 16 years) without presumed intracranial hypertension were included. During

Jo ur

Conclusion

na

HV, ICP decreased significantly (p<0.0001) in the TBI group. An ONSD response was found for HV (p = 0.05).

We observed a dynamic decrease of ONSD during moderate HV. This suggests a potential use of serial ONSD measurements when applying HV in cases of suspected intracranial hypertension.

Keywords: Traumatic brain injury, TBI, Hyperventilation, Intracranial pressure, ICP, optic nerve ultrasound, ONUS, optic nerve sheath diameter, ONSD, point of care ultrasound, POCUS.

Journal Pre-proof

INTRODUCTION Several pathological conditions such as traumatic brain injury, intracranial haemorrhage, stroke or tumours may cause an elevation of intracranial pressure (ICP) with potentially life-threatening consequences. Elevated ICP causes secondary brain injury and is associated with poor outcome [1]. Invasive monitoring with an intracranial device, such as a ventriculostomy or an intraparenchymal probe, remains the only method for continuous ICP measurement in the intensive care unit (ICU). However, such ICP monitoring requires an access hole, which has to be drilled into the skull vault, along with a wire or catheter that is passed through cerebral tissue. The cost and

of

the highly invasive nature of this technique with associated potential morbidity currently restrict its utility to

ro

specialized intensive care units [2]. Interest in developing non-invasive devices and techniques for the detection and assessment of elevated ICP is ongoing [3, 4]. In this context, ultrasonography of the optic nerve sheath

-p

diameter (ONSD) has attracted increasing attention over the past few years as a non-invasive bedside screening

re

tool for the diagnosis of intracranial hypertension [5-11]. The feasibility and utility of ONSD measurements have been investigated in a recent meta-analysis [12]. Data available to date point out that ONSD findings must be

lP

interpreted with caution.

Since the optic nerve is surrounded by cerebrospinal fluid (CSF), any increase in ICP directly influences ONSD

na

due to transmission of the CSF pressure through the subarachnoid space to the retrobulbar segment [13, 14]. Carbon dioxide (CO2), a potent cerebral vasodilator, contributes to ICP-changes via modulation of cerebral blood

Jo ur

flow [15]. To date, the dynamic responsiveness of ONSD to acute changes in intracranial compliance induced by changes in CO2 has received little investigative attention. It has been addressed in small studies in healthy volunteers [16], patients undergoing general anaesthesia [17] and Liver Transplant Recipients [18], all supporting the dynamic responsiveness of ONSD to CO2 changes. The present prospective trial tested whether optic nerve ultrasound (ONUS) is a reliable tool for detecting dynamic changes in ONSD during short-term HV in patients with severe TBI and concomitant invasive ICP monitoring. The dynamic responsiveness of ONSD during an intervention influencing ICP is of potentially great interest when ONSD is used as an alternative to invasively measured ICP.

Journal Pre-proof

MATERIALS AND METHODS The Institutional Ethics Committee of Zurich approved the research protocol of this prospective clinical trial (KEK-ZH 2012-0542) conducted between March 2013 and February 2016. Informed consent was obtained from the next of kin prior to study enrollment and/or from the patient after ICU discharge. The main goal of the study was to quantify potential side adverse effect of moderate HV during the acute phase of the severe TBI on cerebral hemodynamics, oxygenation, and metabolism [19]. ONSD measurements were taken

of

according to the study protocol to evaluate the effect of HV on ONSD.

ro

Patient population

-p

Patients (≥ 18 years of age), under mechanical ventilation (MV) with FIO2 < 60% and PEEP < 15 cmH2O were

re

eligible. Patients with non-penetrating head injury, an initial GCS < 9 prior to sedation and intubation, and extended neuromonitoring with ICP, PbrO2 and/or microdialysis probes were included in the TBI group. Exclusion

lP

criteria included a previous decompressive craniectomy, pregnancy, pre-existing neurologic disease (including previous TBI), acute cardiovascular disease, severe respiratory failure, acute or chronic liver disease, sepsis and

na

orbital injury interfering with ONSD measurements. Patients with persisting hypovolemia or hemodynamic instability despite previous fluid resuscitation (defined as Global End-Diastolic Volume Index < 680 ml/m2, central

Jo ur

venous oxygen saturation (ScvO2) < 60% or increase in mean arterial blood pressure (MAP) > 15% after passive leg raise test) were also excluded. Patients in the TBI group were treated according to a cerebral perfusion oriented protocol aiming to achieve CPP > 70 mmHg, ICP ≤ 20 mmHg. PaCO2 targeted was 4.8-5.2 kPa. According to local practice, TBI patients were ventilated in volume controlled mode, while pressure controlled mode was applied in patients included in the control group.

Monitoring MAP, ICP, CPP, arterial oxygen saturation (SaO2) and end-tidal CO2 (etCO2) were continuously monitored. ICP was measured with a fiber-optic device (Camino, San Diego, CA, USA). ONSD examinations were performed bilaterally by SK or GB, using a 4-12 MHz Probe (Philips CX 50). ONUS was performed by application of ultrasound gel onto both closed upper eyelids and placement of the ultrasound

Journal Pre-proof probe on the temporal area of the eyelid. Once the optic nerve sheath was identified, the optic nerve diameter (OND) and ONSD were measured 3mm behind the retina in an axial plane. The delta ONSD - OND ( (ONSD – OND)) was calculated. Two repeated measurements were performed for each side. In patients without intracerebral lesions or bilaterally injured cerebral hemispheres on CT-scan, the mean value of all measurements was used for analyses. In patients with unilateral lesions, only the measurement on the injured side was used for analyses. Images were reviewed and ONSD measurement was performed, when a clear differentiation of ONSD and OND

of

was given. Insufficient images were excluded from further analysis.

ro

Study protocol

Patients were included in the study within 36 hours of intubation (both groups) and trauma (TBI group) (Figure

-p

1). First, an examination of the ONSD was performed under baseline conditions (A). Afterwards, alveolar

re

ventilation was increased to obtain moderate HV by a stepwise increase in tidal volumes and respiratory rate until a reduction of the etCO2 of 0.7kPa was achieved (B). After 10 minutes of stable etCO2, ONSD measured a second

lP

time. The etCO2 value was kept stable for 40 minutes, followed by a third ONSD examination (D). Finally, normoventilation was re-established over 10 minutes and all variables were allowed to return to baseline (E). A

na

final ONSD examination was conducted at this point. For all time points, MAP, SpO2, etCO2 and ICP (TBI group) were recorded. Control patients were assessed as described except for an additional moderate hypoventilation

Jo ur

maneuver targeting an increase in etCO2 of 0.7kPa above baseline. Arterial blood gas tests (ABG) were obtained at points A, C, D and E, to monitor the changes of pH and P aCO2.

Statistical analysis Effects of HV in the TBI and control groups, as well as hyper- and hypoventilation in the control group, were tested using linear mixed effects model analysis [20]. In the former model, ventilation protocol and patient group were entered as independent variable fixed effects without analysis for interaction. In the latter model, ventilation protocol was entered as independent variable fixed effect. In both models, intercepts for subjects and per-subject random slopes for the effect on dependent variables were employed as random effects. Visual inspection of residual plots did not reveal any obvious deviations from homoscedasticity or normality. P values for fixed effects were obtained by Satterthwaite approximation [21] [22]. ONSD parameters and ICP were tested for correlation by linear

Journal Pre-proof Pearson’s product-moment correlation. Receiver operating characteristic analysis and calculation of the area under the curve served to describe ONUS parameters predicting elevated ICP. Fisher’s exact test was used for comparison of categorical variables. A two-sided p of 0.05 or less was considered statistically significant. For all statistical analyses a fully scripted data management pathway was created within the R environment for statistical computing, version 3.4.2 [23]. Linear mixed effects modeling was performed using the R library lme4, version 1.1.13 [20]. Receiver operating characteristics analysis was performed using the R library plotROC version 2.2.1 [24]. Graphical output was generated using the R library ggplot2, version 2.2.1 [25]. Values are given as mean ±

of

SD.

ro

Results

-p

During the study period, 628 patients with TBI were admitted to the surgical ICU, of those 82 patients with ICP monitoring. Of those, 22 patients were excluded as first GCS was ≥ 9, 21 patients due to decompressive

re

craniectomy, 24 patients because no PbrO2 and/or microdialysis probes were installed, 1 patient because no

lP

approved information, and 3 patients due to TBI > 36 h as previously described in detail [19]. After exclusion of a further patient due to orbital hematoma, 10 patients were included in the TBI group. Patient characteristics for

na

the control group and patients with TBI are presented in table 1. In seven of the ten TBI patients, the CT-scan on

affected.

Jo ur

admission identified bilaterally injured hemispheres, whereas in three patients only the left hemisphere was

Twelve patients were included in the control group. Of these, two patients were excluded because of a previous history of TBI.

Mean ICP in the TBI group was 16.5 ± 6.0 mmHg and decreased significantly to 10.2 ± 7.1mmHg (< 0.0001) during HV. MAP was higher in the TBI group as compared to the control group (p = 0.002), but remained similar across normo-, and hyperventilation and in course of hypoventilation for the control group. ONSD and  (ONSD – OND) at baseline and during HV were similar in the control and TBI groups (p = 0.83 and p = 0.15 for ONSD and  (ONSD – OND), respectively). HV decreased ONSD with a maximum effect at 50 min (p = 0.05, Table 2). The estimated effect for HV after 10 and 50 min was a decrease of ONSD of 0.1 and 0.16 mm and a decrease of  (ONSD – OND) of 0.02 and 0.08 mm. In the control group, hypoventilation increased  (ONSD – OND) with a maximum effect at 5 min (p = 0.01, Table 2). The estimated effect for hypoventilation after

Journal Pre-proof 10 and 50 min was an increase of ONSD of 0.19 and 0.21 mm and of  (ONSD – OND) of 0.34 and 0.12 mm (Table 3). The correlation between ONSD,  (ONSD – OND) and ICP at baseline and during HV is presented in figure 2.  (ONSD – OND) and ICP showed good correlation (r=0.65, p=0.01), while no significant correlation was found between ONSD and ICP in this population (r=0.25, p=0.32). In accordance with current international guidelines [26], a ROC curve for detection of ICP > 22 was calculated (Figure 3). For ONSD, the AUC was 0.64 with a suggested cut-off of ONSD 6.4 mm in our study population. For  (ONSD – OND), an AUC of 0.79 was found

of

with a suggested cut-off of 3.1 mm.

ro

Discussion

-p

Main findings

re

In the present study, we demonstrated in a small group of patients that nervus opticus ultrasound is a reliable tool for detecting dynamic changes in ONSD in correlation with alterations in arterial CO2. This is of particular interest

lP

in patients with TBI, when ONSD could be used as an alternative means of investigation to invasive ICP measurements during HV. We found that a moderate degree of HV was sufficient to decrease ICP significantly (<

na

0.0001). Furthermore, we measured a decrease of ONSD during HV (p=0.05), and an increase of  (ONSD –

Jo ur

OND) during hypoventilation (p = 0.01).

Out data in correlation with current literature ONSD for non-invasive measurement and detection of intracranial hypertension has attracted increasing interest over the last few years. However, the sonographic assessment of ONSD to detect elevated ICP is not standardized. Previous studies suggested various ONSD cut-off values for detection of elevated ICP [5-11]. Interestingly, these values are lower than the values we measured at the baseline in the control group. The values we measured are instead comparable to the values reported in a previous study comparing sonographic and MRI measurements of ONSD in healthy volunteers [27]. These conflicting results suggest that local factors, such as the settings of the ultrasound device or the site of measurement, influence the values of the ONSD measurements and possibly explain inter-study differences. Recently, a comprehensive review concerning detection of high ICP in TBI patients was published [12]. Based on data from seven prospective studies (320 patients) [5-11], the review reported on the potential use of ONSD for the detection of increased ICP. However, since ONSD thresholds for detection of elevated ICP, and even the

Journal Pre-proof definition of elevated ICP vary among studies, the measured values can only be interpreted with caution. As ONSD measurements are parameters close to the detection level values, we evaluated the idea of using  (ONSD – OND) rather than ONSD, as OND is a constant parameter, regardless of ICP. Though strongly limited due to our small study population, correlation of ICP and  (ONSD – OND) with r=0.65 and ROC analysis with an AUC of 0.79 was satisfactory in our population, suggesting that  (ONSD – OND) might provide more reliable estimation of ICP than ONSD. Furthermore, we found a wide range of baseline ONSD values in the control group as well as in the TBI group.

of

This is in accordance with previous data [27] and may contribute to the unsatisfactory correlation of ICP and ONSD in our study population.

ro

It is well known that changes in arterial CO2 are vasoactive on cerebral arterioles, affect cerebral blood volume

-p

and thereby ICP [28]. Nevertheless, the responsiveness of ONSD as a function of arterial CO2 has hardly been investigated. A study of ONSD in 10 spontaneously breathing volunteers in the setting of hyper- and hypocapnia

re

was performed by Dinsmore et al [16]. While hypercapnia induced a rapid increase in ONSD, hypocapnia did not

under anesthesia [17].

lP

change it. On the other hand, ONSD was shown to respond rapidly to induced hypocapnia in fourteen patients

na

In our study, ONSD at baseline with a comparable PaCO2 did not differ between the group of patients with and without TBI. This finding is not surprising, as the majority of the included patients with TBI did not present with

Jo ur

an elevated ICP. Performing a controlled, moderate HV led to a dynamic decrease in ONSD (p=0.05). On the contrary, hypoventilation in the control group did not significantly influence ONSD, while an increase in  (ONSD – OND) (p = 0.01) was found.

The estimated overall effect of HV over 10 and 50 minutes showed a decrease of ONSD and  (ONSD – OND) (0.1 and 0.16 mm for ONSD; 0.02 and 0.08 mm for  (ONSD – OND)), while the estimated effect of hypoventilation showed an increase of ONSD and  (ONSD – OND) (0.19 and 0.21 mm for ONSD and 0.34 and 0.12 mm for  (ONSD – OND). This finding supports the overall effect of ventilatory interventions on ONSD and  (ONSD – OND). However, these findings need cautious interpretation due to the small study population, but they encourage further investigation in a larger study population powered for analysis of dynamic ONSD changes. The use of dynamic changes in ONSD may be beneficial in cases of suspected or not excluded elevated ICP to target a reasonable presumed decrease in ICP, e.g. in the prehospital setting or in cases of absent ICP and PaCO2 monitoring.

Journal Pre-proof Limitations ONSD measurements were taken during our study aiming to quantify potential side adverse effect of moderate HV during the acute phase of the severe TBI, focusing on cerebral hemodynamics, oxygenation, and metabolism [19]. Thus, the study was not powered for ONSD measurements, which limits the findings of this study. Moreover, the small sample size limits the generalizability of the findings and increases the risk of Type II errors. Investigations in the context of intracranial hypertension and in a larger study population are warranted.

of

Conclusion A dynamic decrease in ONSD during moderate HV was observed in our group of TBI patients and the control

Jo ur

na

lP

re

-p

autoregulation in cases of suspected intracranial hypertension.

ro

group. This suggests a potential use of serial ONSD measurements to monitor HV-induced changes in cerebral

Journal Pre-proof Declarations Ethics approval and consent to participate: The Institutional Ethics Committee of Zurich approved the research protocol of this prospective clinical trial (KEK-ZH 2012-0542). Informed consent was obtained from the next of kin prior to study enrollment and/or from the patient after ICU discharge. Consent for publication: Not applicable Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests.

of

Funding: none

ro

Authors' contributions: GB helped in the conception and design of the study, the acquisition and interpretation of data, and revising the work critically for key content.

re

and revising the work critically for key content.

-p

SK helped in the conception and design of the study, the acquisition and interpretation of data, in drafting the work

PB helped in the interpretation of data and revising it for key content.

lP

MH helped in the analysis and interpretation of data, and in revising the work for key content. UB helped in drafting the manuscript and critical revision of key content.

na

RAS helped in interpretation of data and revising it for key content

Jo ur

Acknowledgements: not applicable

Journal Pre-proof

[8]

[9]

[10]

[11]

[12]

[13] [14] [15]

[16]

[17]

[18]

[19] [20] [21] [22] [23] [24]

of

[7]

ro

[6]

-p

[5]

re

[4]

lP

[3]

na

[2]

Marmarou A AR, Ward JD, Choi SC, Young HF, Eisenberg HM, et al. Impact of ICP instability and hypotension on outcome in patients with severe head trauma. Journal of Neurosurgery 1991;75(SUPPL.):S59–S66. Munch E, Weigel R, Schmiedek P, Schurer L. The Camino intracranial pressure device in clinical practice: reliability, handling characteristics and complications. Acta Neurochir (Wien) 1998;140(11):1113-9; discussion 9-20. Kristiansson H, Nissborg E, Bartek J, Jr., Andresen M, Reinstrup P, Romner B. Measuring elevated intracranial pressure through noninvasive methods: a review of the literature. J Neurosurg Anesthesiol 2013;25(4):372-85. Khan MN, Shallwani H, Khan MU, Shamim MS. Noninvasive monitoring intracranial pressure - A review of available modalities. Surg Neurol Int 2017;8:51. Kimberly HH, Shah S, Marill K, Noble V. Correlation of optic nerve sheath diameter with direct measurement of intracranial pressure. Acad Emerg Med 2008;15(2):201-4. Moretti R, Pizzi B. Optic nerve ultrasound for detection of intracranial hypertension in intracranial hemorrhage patients: confirmation of previous findings in a different patient population. J Neurosurg Anesthesiol 2009;21(1):16-20. Rajajee V, Vanaman M, Fletcher JJ, Jacobs TL. Optic nerve ultrasound for the detection of raised intracranial pressure. Neurocrit Care 2011;15(3):506-15. Robba C, Cardim D, Tajsic T, Pietersen J, Bulman M, Donnelly J, et al. Ultrasound non-invasive measurement of intracranial pressure in neurointensive care: A prospective observational study. PLoS Med 2017;14(7):e1002356. del Saz-Saucedo P, Redondo-Gonzalez O, Mateu-Mateu A, Huertas-Arroyo R, Garcia-Ruiz R, BotiaPaniagua E. Sonographic assessment of the optic nerve sheath diameter in the diagnosis of idiopathic intracranial hypertension. J Neurol Sci 2016;361:122-7. Jeon JP, Lee SU, Kim SE, Kang SH, Yang JS, Choi HJ, et al. Correlation of optic nerve sheath diameter with directly measured intracranial pressure in Korean adults using bedside ultrasonography. PLoS One 2017;12(9):e0183170. Geeraerts T, Launey Y, Martin L, Pottecher J, Vigue B, Duranteau J, et al. Ultrasonography of the optic nerve sheath may be useful for detecting raised intracranial pressure after severe brain injury. Intensive Care Med 2007;33(10):1704-11. Robba C, Santori G, Czosnyka M, Corradi F, Bragazzi N, Padayachy L, et al. Optic nerve sheath diameter measured sonographically as non-invasive estimator of intracranial pressure: a systematic review and meta-analysis. Intensive Care Med 2018;44(8):1284-94. Helmke K, Hansen HC. Fundamentals of transorbital sonographic evaluation of optic nerve sheath expansion under intracranial hypertension II. Patient study. Pediatr Radiol 1996;26(10):706-10. Hansen HC, Helmke K. The subarachnoid space surrounding the optic nerves. An ultrasound study of the optic nerve sheath. Surg Radiol Anat 1996;18(4):323-8. Klinzing S SF, Steiger P, Pagnamenta A, Bèchir M, Brandi G. Transcranial color-coded duplexsonography assessment of cerebrovascular reactivity to carbon dioxide: a prospective interventional study

Jo ur

[1]

Dinsmore M, Han JS, Fisher JA, Chan VW, Venkatraghavan L. Effects of acute controlled changes in end-tidal carbon dioxide on the diameter of the optic nerve sheath: a transorbital ultrasonographic study in healthy volunteers. Anaesthesia 2017;72(5):618-23. Kim JY, Min HG, Ha SI, Jeong HW, Seo H, Kim JU. Dynamic optic nerve sheath diameter responses to short-term hyperventilation measured with sonography in patients under general anesthesia. Korean J Anesthesiol 2014;67(4):240-5. Seo H, Kim YK, Shin WJ, Hwang GS. Ultrasonographic optic nerve sheath diameter is correlated with arterial carbon dioxide concentration during reperfusion in liver transplant recipients. Transplant Proc 2013;45(6):2272-6. Brandi G, Stocchetti N, Pagnamenta A, Stretti F, Steiger P, Klinzing S. Cerebral metabolism is not affected by moderate hyperventilation in patients with traumatic brain injury. Crit Care 2019;23(1):45. Bates D MM, Bolker B, Walker S. Fitting Linear Mixed-Effects Models using lme4. J Stat Softw 67 2015. Baayen RH DD, Bates DM. Mixed-effects modeling with crossed random effects for subjects and items. J Mem Lang 59 2008:390–412. Barr DJ LR, Scheepers C, Tily HJ. Random effects structure for confirmatory hypothesis testing: Keep it maximal. J Mem Lang 2013;68. Team RDC. A language and environment for statistical computing. A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2011. MC S. plotROC: A Tool for Plotting ROC Curves, 2017.

Journal Pre-proof

of ro -p re

[28]

lP

[27]

na

[26]

H W. ggplot2: Elegant Graphics for Data Analysis. Springer, New York 2010(1st ed. 2009. Corr. 3rd printing 2010 edition). Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery 2017;80(1):6-15. Bauerle J, Schuchardt F, Schroeder L, Egger K, Weigel M, Harloff A. Reproducibility and accuracy of optic nerve sheath diameter assessment using ultrasound compared to magnetic resonance imaging. BMC Neurol 2013;13:187. Stocchetti N, Maas AI, Chieregato A, van der Plas AA. Hyperventilation in head injury: a review. Chest 2005;127(5):1812-27.

Jo ur

[25]

Journal Pre-proof Figure 2. In TBI patients at baseline and during hyperventilation, a good correlation between ICP and  (optical nerve sheath diameter – optical nerve diameter) was found (Figure 1A, r =

Jo ur

na

lP

re

-p

ro

of

0.65, p = 0.01), but not for optical nerve sheath diameter (Figure 1B, r = 0.25, p = 0.32).

Journal Pre-proof

ro

of

Figure 3. Receiver operating characteristic analysis for prediction of ICP > 22 revealed an area under the curve of 0.79 for  (optical nerve sheath diameter – optical nerve diameter) and 0.64 for optical nerve sheath diameter. A cutoff of 6.4 mm for optical nerve sheath diameter and 3.1 mm for  (optical nerve sheath diameter – optical nerve diameter) is suggested.

Jo ur

na

lP

re

-p

dONSD,  (optical nerve sheath diameter – optical nerve diameter); ONSD optical nerve sheath diameter.

Journal Pre-proof Table 1: Patient characteristics. Control group n = 10

TBI group n = 10

p

45 ± 16

35 ± 14

0.12

Sex (female)

6/10

3/10

0.37

BMI [kg m-2]

23.1 ± 2.5

24.0 ± 2.7

0.46

Simplified acute physiology score II

26.5 ± 10.6

46.6 ± 7.8

< 0.001

Glasgow coma scale at ICU admission

-

5.9 ± 2.8

-

Injury severity score

-

30 ± 11

-

0/10

Age [a]

-

Pressure controlled continuous mandatory ventilation

10/10

-

Volume controlled continuous mandatory ventilation

0/10

of

Ventilator mode

< 0.0001

10/10

ro

Values are given as mean ± SD. P values were calculated using Satterthwaite’s approximation

-p

for fixed effects or using fisher’s exact test for categorical variables. TBI, traumatic brain

Jo ur

na

lP

re

injury; BMI, body mass index; ICU, intensive care unit.

Journal Pre-proof Table 2. Optical nerve sheath diameter, optical nerve diameter, and  (optical nerve sheath diameter – optical nerve diameter) during normo- and hyperventilation in TBI patients and controls, and hypoventilation in controls. Normoventilation A

Hyperventilation (10 min) C

Hyperventilation (50 min) D

Normoventilati Hypoventilation Hypoventilation on (10 min) (50 min) A C D

p (TBI)

p (Hyper10)

p (Hyper50)

p p (Hypo(Hypo-50) 10)

TBI n = 10

Controls n = 10

TBI n = 10

Controls n = 10

TBI n = 10

Controls n = 10

Controls n = 10

Controls n = 10

Optical nerve sheath diameter [mm]

5.73 ± 0.68

5.79 ± 0.83

5.83 ± 0.25

5.62 ± 0.6

5.74 ± 1

5.6 ± 0.66

5.64 ± 0.86

5.95 ± 0.15

6.1 ± 0.07

0.83

0.23

0.05

0.24

0.28

 (optical nerve sheath diameter – optical nerve diameter) [mm]

2.63 ± 0.48

2.91 ± 0.33

2.56 ± 0.34

2.64 ± 0.32

2.82 ± 0.52

2.57 ± 0.43

2.73 ± 0.49

2.94 ± 0.16

2.79 ± 0.09

0.15

0.84

0.36

0.01

0.44

ICP [mmHg]

-

16.5 ± 6.0

-

10.2 ± 7.1

-

10.22 ± 7.14

-

-

-

-

< 0.0001

< 0.0001

-

-

PaCO2 [kPa]

5.24 ± 0.61

4.99 ± 0.25

4.96 ± 0.37

4.44 ± 0.59

4.33 ± 0.27

4.04 ± 0.63

4.12 ± 0.4

5.5 ± 0.23

5.7 ± 0.35

0.76

< 0.0001

< 0.0001

0.02

< 0.001

5.52 ± 0.91

4.92 ± 0.75

5.22 ± 0.9

4.58 ± 0.94

4.2 ± 0.65

4.3 ± 0.8

3.94 ± 0.81

5.8 ± 0.78

6.2 ± 0.7

0.22

< 0.0001

pH [1]

7.36 ± 0.05

7.37 ± 0.1

7.39 ± 0.05

7.42 ± 0.05

7.45 ± 0.02

7.45 ± 0.05

7.46 ± 0.03

7.35 ± 0.03

7.36 ± 0.02

0.40

< 0.0001

< 0.0001

0.14

0.007

PaO2 [kPa]

17.77 ± 4.6

17.26 ± 1.61

17.1 ± 2.91

18.65 ± 4.37 17.77 ± 2.04

17.56 ± 4.65

18.77 ± 2.6

16.12 ± 3.52

14.43 ± 2.84

0.92

0.25

0.33

0.35

0.43

97.7 ± 1.89

99 ± 0.45

98.2 ± 2.49

98.4 ± 2.01

Heart rate [min 1 ] MAP [mmHg]

-

74.3 ± 17.81 74.11 ± 16.9 71.4 ± 13.96 74.9 ± 20.63 76 ± 10.79

91.78 ± 8.69 73.6 ± 10.16 78.1 ± 11.57

99.45 ± 0.39

98.4 ± 2.01

99.52 ± 0.28

98.25 ± 1.71

97.33 ± 2.31

0.09

0.02

0.02

0.58

0.15

73.56 ± 18.26

76.5 ± 22.54

73.67 ± 18.43

79.25 ± 15.37

76 ± 22

0.84

0.81

0.69

0.01

0.09

93.22 ± 11.18

76.7 ± 14.07

91.11 ± 9.2

71.25 ± 12.47

71.67 ± 11.5

0.002

0.30

0.89

0.23

0.21

re

SaO2 [%]

ro

EtCO2 [kPa]

< < 0.0001 < 0.0001 0.0001

-p

of

Controls n = 10

lP

Values are given as mean ± SD. P values for individual fixed effects were calculated using Satterthwaite’s approximation in a model comprising of normo- and hyperventilation

na

protocols in TBI patients and controls, and a model of normo-, hyper- and hypoventilation protocol in controls. Hyper-10 and 50, hyperventilation for 10 and 50 minutes; hypo-10 and

Jo ur

50, hypoventilation for 10 and 50 minutes; TBI, traumatic brain injury; ICP, intracranial pressure; PaCO2, arterial carbon dioxide partial pressure; EtCO2, end-tidal carbon dioxide partial pressure; PaO2, arterial oxygen partial pressure; SaO2, arterial oxygen saturation; MAP, mean arterial pressure.

Journal Pre-proof Table 3. Parameters of mixed linear model analysis as measures of the effect of ventilation protocol on optical nerve and nerve sheath diameters. TBI

Hyperventilation (10 min)

Hyperventilation (50 min)

Hypoventilation (10 min)

Hypoventilation (50 min)

estimate (CI)

t statistic

df

estimate (CI)

t statistic

df

estimate (CI)

t statistic

df

estimate (CI)

t statistic

df

estimate (CI)

t statistic

df

Optical nerve sheath diameter [mm]

0.07 ± 0.32 (-0.47 - 0.6)

0.21

19.0

-0.1 ± 0.08 (-0.23 - 0.04)

-1.21

40.1

-0.16 ± 0.08 (-0.3 - -0.03)

-2.00

40.1

0.19 ± 0.16 (-0.08 - 0.46)

1.19

39.1

0.21 ± 0.19 (-0.11 - 0.53)

1.10

39.2

 (optical nerve sheath diameter – optical nerve diameter) [mm]

0.24 ± 0.16 (-0.03 - 0.51)

1.50

18.5

-0.02 ± 0.09 (-0.16 - 0.13)

-0.20

37.1

-0.08 ± 0.09 (-0.24 - 0.07)

-0.93

37.7

0.34 ± 0.13 (0.12 - 0.56)

2.62

39.3

0.12 ± 0.16 (-0.14 - 0.38)

0.78

39.4

Jo ur

na

lP

re

-p

ro

of

TBI, traumatic brain injury; CI, confidence interval; df, degrees of freedom.

Journal Pre-proof

lP

re

-p

ro

of

 Ultrasonography of the optic nerve sheath diameter (ONSD) has attracted increasing attention The dynamic responsiveness of ONSD during an intervention influencing ICP is of interest when ONSD is used as an alternative to invasively measured ICP

na



Development of non-invasive devices and techniques for the detection and assessment of elevated ICP is of interest

Jo ur



Figure 1

Figure 2

Figure 3