Netherlands Journal of Critical Care

Volume 26 - No 2 - March 2018

Bi-monthly journal of the Dutch Society of Intensive Care

REVIEW ORIGINAL ARTICLE CASE REPORT Ultrasound imaging of the diaphragm: facts and To see or not to see: ultrasound-guided Hepatopulmonary syndrome – a rare cause of future: A guide for the bedside clinician percutaneous tracheostomy hypoxaemia M.E. Haaksma, L. Atmowihardjo, L. Heunks, J.E. Lopez Matta, C.V. Elzo Kraemer, D.J. van Westerloo W.A.C. Koekkoek, C.R. Lamers, R. Meiland, A. Spoelstra-de Man, P.R. Tuinman M.J. van der Veen, D.C. Burgers – Bonthuis 2018

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EXECUTIVE EDITORIAL BOARD N.P. Juffermans, editor in chief CONTENTS I. van Stijn, managing editor H. Dupuis, language editor J. Horn, editorial board EDITORIAL A.P.J. Vlaar, editorial board 56 The golden age of ultrasound is only just beginning M. Kuiper, associate editor P. Spronk, associate editor F.H. Bosch, P.R. Tuinman

[email protected] REVIEW COPYRIGHT 58 Ultrasound imaging of the diaphragm: facts and future: A guide for the bedside clinician Netherlands Journal of Critical Care ISSN: 1569-3511 M.E. Haaksma, L. Atmowihardjo, L. Heunks, A. Spoelstra-de Man, P.R. Tuinman NVIC p/a Domus Medica P.O. Box 2124, 3500 GC Utrecht T: +31-(0)30 - 282 38 38 ORIGINAL ARTICLE 66 To see or not to see: ultrasound-guided percutaneous tracheostomy © 2018 NVIC. All rights reserved. Except as outlined below, no part of this publication may J.E. Lopez Matta, C.V. Elzo Kraemer, D.J. van Westerloo be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording CASE REPORT or otherwise, without prior written permission of 70 Pneumatosis intestinally, to treat or not to treat? the publisher. Permission may be sought directly N. Treskes, B. Festen-Spanjer from NVIC.

DERIVATIVE WORKS CASE REPORT Subscribers may reproduce tables of contents or prepare lists of articles including abstracts 74 Bilateral vocal cord palsy: An uncommon late complication of cortical ischaemic stroke for internal circulation within their institutions. V. Jain, V. Jain, H. Sapra Permission of the publisher is required for resale or distribution outside the institution. Permission of the publisher is also required for all other CASE REPORT derivative works, including compilations and translations. 77 Hepatopulmonary syndrome – a rare cause of hypoxaemia W.A.C. Koekkoek, C.R. Lamers, R. Meiland, M.J. van der Veen, D.C. Burgers – Bonthuis ELECTRONIC STORAGE Permission of the publisher is required to store or NVIC use electronically any material contained in this RESEARCH NEWS journal, including any article or part of an article. 81 Lung recruitment and titrated PEEP in moderate to severe ARDS SUBSCRIPTIONS J. Pillay NAJAARSCONGRES An annual subscription to the Netherlands Journal of Critical Care consists of 6 issues. Issues within Europe are sent by standard mail and CORRESPONDENCE outside Europe by air delivery. Cancellations should be made, in writing, at least two months 83 Pro/con debate before the end of the year. Conservative oxygenation in the intensive care unit: Pro The annual subscription fee for the Netherlands 13 september 2018 is 5 170, for Europe 5 285, for the rest of the world H.J.F. Helmerhorst 5 380. Subscriptions are accepted on a prepaid basis only and are entered on a calendar year basis. Please transfer the fee to ABNAMRO NL55 ABNA CORRESPONDENCE 0524 5618 93, swift-code: ABNANL2A. Do not 86 Pro/con debate forget to mention the complete address for delivery of the Journal. Conservative oxygenation in the intensive care unit: Con A.M.E. Spoelstra – de Man CLAIMS Claims for missing issues should be made within two months of the date of dispatch. Missing issues will be mailed without charge. Issues claimed beyond the two-month limit must be prepaid at 88 NVIC conference and course agenda back copy rates. 89 Editorial board

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NVIC_SAVE THE DATE 2018_210x275_TBV_NJCC_MAGAZINE.indd 1 08-03-18 18:39 Netherlands Journal of Critical Care Submitted January 2018; Accepted February 2108

EDITORIAL

The golden age of ultrasound is only just beginning

F.H. Bosch1, P.R. Tuinman2,3,4 1Department of Intensive Care Medicine, Rijnstate Hospital, Arnhem, the Netherlands 2Department of Intensive Care, 3Research Vumc Intensive Care (REVIVE) and, 4Amsterdam Cardiovascular Sciences, Vu Medical Center, Amsterdam, the Netherlands

Correspondence F.H. Bosch: [email protected]

Keywords - ultrasound, intensive care, training, intervention

In the last 10 years, many intensivists have learned that using is also very useful for teaching physiological phenomena. ultrasound in their daily practice leads to faster diagnosis and Determining the flow pattern in an artery, vein or aortic outflow safer patient care.[1,2] Many algorithms have been developed trajectory is helpful in understanding physiology.[6] for the structured approach of the care of an unstable patient. Often people warn about the risks of performing ultrasound Examples of these algorithms are RACE (Rapid Assessment without adequate training. The risk of a wrong diagnosis cannot with Cardiac Echo), FATE (Focus Assessed Transthoracic be underestimated and we agree with these critics that adequate Echo), FAST (Focussed Assessment with Sonography in training is mandatory and should be part of every doctor’s Trauma), and BLUE (ultrasound of the lung in a cyanotic patient curriculum.[7] This is in line with the policy of the Dutch Society without a history of pulmonary disease). Nowadays, diagnostic of Intensive Care with stimulates its members to follow not only ultrasound performed by intensivists is usually called POCUS a beginners course but also an advanced course. (Point of Care UltraSound). What exactly is being covered in this acronym is, however, still being debated. We feel that the golden age of ultrasound is just beginning. There are some developments that have led to more routine use of Ultrasound is also increasingly used during interventions such ultrasound in daily practice. The price of an ultrasound machine as central vein cannulation, insertion of arterial catheters and is decreasing; miniaturisation, digitalisation, connection of drainage of pleural or abdominal fluids. For example, in recent ultrasound equipment with the electronic health record through years it has been demonstrated that possible complications WiFi, etc., all lead to an everincreasing use. More and more doctors of central vein cannulation can be diagnosed with the use of are being trained in the safe use of this technique and every day ultrasound. If the guidewire is clearly visible within the vein new applications are being developed. and in the right atrium during insertion, if there is visible lung In this issue,[8,9] the Netherlands Journal of Critical Care is starting sliding and if turbulence of injected saline is seen in the right an exciting new series on the use of ultrasound beyond the well- atrium after insertion of the catheter, performing an X-ray of the known indications of heart and lungs; some applications may be thorax after insertion of the catheter does not have additional familiar to you, others may be completely new. We hope that you value and can be safely omitted.[3-5] will find them instructive and that they may stimulate you to use We often wonder what our imaging routine would be like if ultrasound even more. X-ray and ultrasound technology were invented on the same day. We are convinced that, in that case, physicians would References perform an ultrasound in many instances where now an X-ray 1. Charron C, Repesse X, Bodson L, Au SM, Vieillard-Baron A. Ten good reasons why is routinely ordered. everybody can and should perform cardiac ultrasound in the ICU. Anaesthesiol Ultrasound is not only a great diagnostic tool, but it is also Intensive Ther. 2014;46:319-22. 2. Via G, Hussain A, Wells M, et al. International evidence-based recommendations tremendously useful in teaching. Young doctors get a much for focused cardiac ultrasound. J Am Soc Echocardiogr. 2014;27:683 e1- e33. better appreciation of normal and abnormal anatomy. Taking in 3. Ablordeppey EA, Drewry AM, Beyer AB, et al. Diagnostic Accuracy of Central Venous Catheter Confirmation by Bedside Ultrasound Versus Chest Radiography dynamic images of organs, arteries and veins with an ultrasound in Critically Ill Patients: A Systematic Review and Meta-Analysis. Crit Care Med. probe in their hands leads to an insight that cannot be obtained 2017;45:715-24. from anatomy books or post-mortem dissections. Ultrasound

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4. Blans MJ, Endeman H, Bosch FH. The use of ultrasound during and after central 7. Elbers PWG, Kamp O, van der Sluijs JP, Lely R, Tuinman PR. [Should every doctor venous catheter insertion versus conventional chest X-ray after insertion of a be allowed to use ultrasound? Dilemmas surrounding broad application of central venous catheter. Neth J Med. 2016;74:353-7. ultrasound in clinical practice]. NTvG. 2017;161:D1063. 5. Steenvoorden TS, Smit JM, Haaksma ME, Tuinman PR. Necessary additional steps 8. M.E. Haaksma, L. Atmowihardjo, L. Heunks, A. Spoelstra-de Man, P.R. Tuinman, in ultrasound guided central venous catheter placement: getting to the heart of Ultrasound imaging of the diaphragm: facts and future: A guide for the bedside the matter. Crit Care. 2017;21:307. clinician. Neth J Crit Care. 2018;26:58-63 6. So S, Patel RM, Orebaugh SL. Ultrasound imaging in medical student education: 9. J. Lopez Matta, C.E. Kraemer, D.J. van Westerloo, To see or not to see: ultrasound- Impact on learning anatomy and physical diagnosis. Anat Sci Educ. 2017;10:176-89. guided percutaneous tracheostomy. Neth J Crit Care. 2018;26:66-69

Consolidatiecursus echogra e CURSUS onderda aart rida uli rida deceer

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NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 57 Submitted April 2017; Accepted July 2017

REVIEW

Ultrasound imaging of the diaphragm: facts and future. A guide for the bedside clinician

M.E. Haaksma, L. Atmowihardjo, L. Heunks, A. Spoelstra-de Man, P.R. Tuinman Department of Intensive Care Medicine, VU University Medical Center Amsterdam, Amsterdam, The Netherlands

Correspondence M.E. Haaksma - [email protected]

Keywords - diaphragm, ultrasound, mechanical ventilation

Abstract Introduction Introduction: The diaphragm plays a significant role in Diaphragm dysfunction frequently develops in critically ill the ICU setting, as it forms a crucial part in sustaining patients and is associated with adverse outcome, including spontaneous breathing and ability to wean from mechanical prolonged duration of mechanical ventilation and increased ventilation. A lot of research has been conducted to find new length of ICU stay.[1,2] Risk factors for the development approaches and parameters for its assessment. Out of these, of diaphragm dysfunction include sepsis and mechanical ultrasonography has become a popular option due to its many ventilation. Both ventilator over-assist and ventilator under- advantages. In this review, the aim was to provide an extensive assist are associated with development of respiratory muscle summary on our current knowledge on ultrasonography of weakness. Therefore, monitoring diaphragm activity using the diaphragm. Methods of application, feasibility, limitations non-invasive, reproducible methods may be of clinical and future perspectives will be discussed. importantance.[3] Methods: This is a narrative review. A thorough search in PubMed was conducted to find all relevant articles. Filters Currently, several techniques, such as pressure and flow were applied to sort out studies that were conducted in recordings, diaphragm electromyography and chest X-ray are animals or patients younger than 18 years. available for this purpose. However, most of these come with Results: Overall, ultrasonography presents a promising their limitations, such as invasiveness, poor cost-effectiveness imaging technique to assess diaphragm function. Diaphragm and limited bedside availability. Ultrasonography is motion can be used to detect diaphragm dysfunction, increasingly used to visualise several tissues and organs, such paralysis and patient ventilator asynchrony, while thickness as lung, heart, liver and more recently the diaphragm. and the thickening fraction can be used to predict weaning Ultrasound of the diaphragm allows quantification of outcomes and monitor diaphragm strength. Limitations are movement, thickness and thickening fraction, which can potential inaccuracy inherent to the ultrasound machine and be used to estimate diaphragm function. This is relevant in variability between observers, assisted modes of ventilation ICU patients, for example, to predict extubation outcomes or (motion cannot be interpreted) and controlled modes of estimate the work performed by the diaphragm. In particular ventilation (ultrasound not applicable). during weaning, analysis of respiratory muscle function Discussion: While a range of studies are available that may be of clinical relevance, given that around 40% of the demonstrate ultrasonography as a viable tool to assess the time spent in the ICU is used for weaning from mechanical diaphragm, only a few have been conducted in sufficiently ventilation and failure of extubation is related to an increased large and representative patient groups. Further research is risk of death of up to 40-50%, depending on the cause of needed for validation of those ultrasound derived data and failure.[4–6] conclusions. Until then, it is key to consider the limitations In this narrative review, methods for visualising of the of ultrasonography carefully. Nevertheless, ultrasonography diaphragm using ultrasound and its clinical application will be does provide valuable information and should be used to discussed. Evidence on reproducibility and feasibility will be monitor the diaphragm. given and limitations will be listed. Furthermore, suggestions for potential future directives will be provided.

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Methods Table 1. Ultrasound measurements on average diaphragm thickness This is a narrative review. A thorough search in PubMed was No. of patients tdi end expiration tdi end inspiration conducted to find all articles. Filters were applied to sort out Ferrari 20144 46 2.4 mm [1.7 to 3.0] 3.4 mm [2.6 to 4.4] studies that were conducted in animals, patients younger than Goligher 201530 96 2.4 mm (0.8) 2.7 mm (0.8) 18 years or not available in English. Farghaly 201627 56 1.6 mm (1.12–1.87) 2.4 mm (2.2–2.8) How is ultrasound of the diaphragm used? tdi = diaphragm thickness, ( ) = standard deviation, [ ] = range Basic ultrasound offers two approaches to imaging: brightness- mode (B-Mode) and motion-mode (M-mode). Applying these modes to visualise the diaphragm allows assessment of Motion diaphragm thickness (tdi) (B-mode) and diaphragm motion Diaphragm motion is measured in the M-mode with a low (M-mode). frequency probe (1-5 MHz) just below the costal arch on the midclavicular line, with the probe directed cranially and a small Thickness dorsal tilt (figure 2). The lower frequency offers greater depth, but The tdi is measured in B-mode with a high-frequency probe in exchange for less spatial resolution. Measurements of motion (≥10 MHz) in the zone of apposition at the mid-axillary line can only be used in spontaneously breathing patients, as during approximately between the 8th and 11th rib, with slight assisted ventilation active displacement cannot be distinguished variation between patients.[7] In general, obtaining a good view from passive displacement due to driving pressures. will be easier on the patients right side compared with the left Values for motion were assessed during quiet breathing, deep side as the liver provides an excellent ultrasound window. In breathing and voluntary sniffing in healthy non-ventilated the mid-axillary line, the diaphragm is seen as as a structure individuals and are summarised in table 2.[12,13] Slight composed of three different echogenic layers: the pleural differences were found, probably attributable to the difference membrane, a central tendinous layer and the peritoneal in group size. The significant differences between men and membrane (figure 1).[8] The outer layers are used as borders women are caused by differences in height and bodyweight and should not be included in the thickness measurement. and not gender per se.[14] Average values for thickness (table 1) reported in healthy volunteers are 0.19 ± 0.04 cm (95% CI 0.17-0.20) in men and 0.14 ± 0.03 cm (95% CI 0.13-0.15) in women.[9] Marking the site of probe position on the skin significantly improves repeatability and reproducibility of repeated measurements. [10 ] If tdi is measured during maximal inspiratory and expiratory effort, the thickening fraction (%) can be calculated (tdi%

= (tdi,end inspiration -tdi,end expiration)/tdi,endexpiration), which makes interpatient comparisons easier, as thickness varies between individuals.[11] It must be kept in mind however, that during controlled modes of ventilation, this measurement is not feasible, as no contractile activity of the diaphragm is present. Figure 2. M-mode ultrasound of the diaphragm 1) Diaphragm at end expiration; 2) Diaphragm motion; 3) Diaphragm at end inspiration

Table 2. Ultrasound measurements on average diaphragm motion No. of Quiet Voluntary Deep After SBT: patients Breathing sniffing breathing Successful vs failed extubation Gerscovich 23 1.5 cm 1.66 cm 5.69 cm x 200113 [0.26–2.10] [0.48-2.66] [1.67-9.20]

Boussuges 210 1.8 cm 2.8 cm 6.0 cm x 200912 (±0.3) (±0.6) (±1.3)

Farghaly 56 x X x 1.6 cm vs 0.98 cm 201627 Figure 1. B-mode ultrasound of the diaphragm 1) Pleura; 2) Fibrous layer in centre of the diaphragm 3) Peritoneum SBT = Spontaneous Breathing Trial, ( ) = standard deviation, [ ] = range

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What is ultrasound of the diaphragm used for? Several studies have demonstrated a correlation between tdi% Evaluating functionality and PTPdi or work of breathing. Vivier et al.[21] conducted Evaluating diaphragm functionality might be a key aspect their study in 12 patients, each ventilated for at least 48 in the management of ventilated patients, as diaphragm hours. They found a significant correlation (p=0.52, p<0.001) dysfunction has a major impact on outcome.[15] More between the thickening fraction and the PTPdi per breath. specifically, disuse of the muscle results in changes in the However, a closer look at the data reveals that for a given muscle fibre cross-sectional area and an up to 25% reduction amount of effort delivered, the thickening fraction can vary in the pressure generating capacity of the diaphragm in the from 0 to almost 40%. From a physiological perspective, it first 3-4 days of ICU admission.[16-18] should be acknowledged that thickening falls short due to the Given the impact of critical illness on respiratory muscle fact that it does not incorporate the duration and frequency function, the use of ultrasound to diagnose weakness and of breaths, which are components of the PTP. Similar results monitor function is of clinical importance. were found by Umbrello et al.[22] In both studies, effort varied Kim et al.[2] used M-mode ultrasound to quantify diaphragm more strongly during lower levels of pressure support and motion and defined an excursion of 10 mm or less as showed smaller differences in thickening fraction during diaphragm dysfunction. The diaphragm dysfunction group higher levels. showed a longer time spent on ventilation (576 [374-850] vs. For now, the conclusion has to be drawn that ultrasonography 203 [109-408] hours, p<0.01) and prolonged weaning (401 is not sufficiently validated to quantify breathing effort and [226-612] vs. 90 [24-309] hours, p<0.01). Mariani et al.[19] that the circumstances under which ultrasound provides an used the same cut-off value as applied by Kim et al.[2] and estimate of breathing effort require further study. found that diaphragm dysfunction was related to higher ICU mortality rates (37% vs 5%). Weaning and extubation Lerolle et al.[1] demonstrated that diaphragm motion provides Research has shown that ultrasound of the diaphragm can be an excellent and noninvasive method to exclude diaphragm effectively used to predict extubation success in ventilated dysfunction in patients ventilated for more than seven days. patients.11 This is a crucial task, because failure in doing so In their study, diaphragm dysfunction was assessed using is related to longer intubation times and ICU stay.[1] This in the Gilbert Index, which determines the contribution of the turn leads to lung damage and higher risks of infection due to diaphragm during inspiration by measuring pressure swings ventilation and unnecessary sedation.[23] Even mortality rates across it (ΔPgastric/ΔPdiaphragm).[20] Ultrasound proved are influenced by failure of successful extubation.[6] Currently, to have a 100% sensitivity (95% CI, 63 to 100%) and 85% indexes such as the rapid shallow breathing index (RSBI), and specificity (95% CI, 62 to 97%) when <25 mm excursion was the CROP index, composed of factors including compliance, regarded as the cut-off point for diaphragm dysfunction. resistance, oxygenation and pressure and spontaneous breathing trials (SBT) are used. In summary, it can be concluded that loss of diaphragm DiNino et al. measured tdi and calculated tdi% in 63 patients function develops rapidly and is associated with important and chose 30% as the cut-off point for successful extubation. clinical implications. Ultrasound parameters such as tdi This lead to a sensitivity of 88% and a specificity of 71%, thus and diaphragm motion offer a viable option to monitor this being superior to the RSBI.[24] They hypothesised that the decay and perhaps in the future, with increasing knowledge, underlying reason might be that in the RSBI the accessory the possibility to track the effects of interventions aimed at breathing muscles might camouflage the diaphragmatic improving diaphragm function. weakness, which will not be able to take on the capacity of the diaphragm in the long run.[25,26] Work of breathing Ferrari et al.[4] conducted a similar study in patients who Ultrasonography could possibly provide a non-invasive had previously failed weaning trials evaluating tdi% >36%. alternative to measure work of breathing and the pressure as a predictor for successful extubation. This resulted in a time product (PTPdi) (PTPdi per breath = average inspiratory sensitivity and specificity of 88% and 82% respectively. pressure x time / number of breaths) during assisted More recently, Farghaly et al.[27] evaluated diaphragmatic ventilation, which both currently require invasive pressure parameters (tdi, tdi% and diaphragm excursion) in 54 measurements (oesophageal and gastric pressure). These patients who successfully passed SBT. Of these 54 patients, indices provide information about loading of the diaphragm 14 failed to complete extubation. The ideal cut-off point to and allow the clinician to titrate ventilator support, to prevent predict successful extubation for tdi at end inspiration was over- or under-assist of the diaphragm and possibly limit ≥21 mm and for end expiration ≥13.5 mm, yielding a 77.5% disuse atrophy or muscle injury. sensitivity and 86.6% specificity, and an 80% sensitivity and

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50% specificity respectively. A tdi% ≥34.2% provided the precipitate patient-ventilator asynchrony,[31] which aside from highest sensitivity with 90% but only 64.3% specificity. The disuse further damages the diaphragm. These findings suggest tdi combined with excursion, which on its own yielded a that depending on diaphragm strength, adequate magnitudes sensitivity of 87.5% and specificity of 71.5% with a threshold of assistance must be chosen to uphold maximal contractile of ≥10.5 mm, provided a test with a decreased sensitivity of activity whilst avoiding exhaustion or asynchrony. 64.9% but a 100% specificity. With increasing knowledge about possibilities for Thus, three studies evaluated tdi% as a predictor for successful intervention, the aforementioned findings lead us to believe extubation (table 3) and demonstrated that it was superior to that monitoring of the diaphragm could possibly gain a bigger the RSBI .[4,11,27] role in intensive care medicine in the future.

Table 3. Thickening fraction (tdi%) as predictor for successful Is ultrasound of the diaphragm reproducible and extubation feasible? No. of patients tdi% cut-off Sensitivity Specificity Only a few studies have studied the reproducibility and [10] DiNino 201424 63 30% 88% 71% feasibility of tdi and tdi%. In 2015 Goligher et al. addressed exactly this issue. They assessed repeatability (within Ferrari 20144 46 36% 88% 82% observer) and reproducibility (between observers). The Farghaly 201627 54 34% 90% 64% results were satisfactory, but marking the site of measurement greatly increased the repeatability as well as reproducibility tdi% = thickening fraction coefficients (1.9 to 0.2 and 1.4 to 0.4 respectively), which indicate that 95% of the differences in repeated measurements Spadaro et al.[28] introduced a new way of predicting weaning by the same observer (repeatability) or by two different success through diaphragm motion by combining it with observers (reproducibility) will be equal to or less than that the RSBI. They substituted tidal volume in the denominator coefficient.[10] for motion and named the index D-RSBI (= respiratory rate / motion in mm). The predictive values found were a 94.1% Based on their findings, they concluded that tdi was very sensitivity (71.3-99.9) and a 64.7% specificity (46.5-80.3), reproducible and repeatable, while tdi% was less so. The most surpassing values for motion as well as the RSBI and coming likely reason is that the calculation of tdi% incorporates the close to thickening fraction as a predictor for weaning. error of measurements during inspiration and expiration. Some of these are inherent to the ultrasound machine and cannot be Monitoring circumvented. The highest resolution most machines have lies Ultrasonography can be used for monitoring the diaphragm around 0.1 mm (given that the speed of soundwaves averages and offers certain advantages over other currently used 1540 m/s in human tissue, the range of high frequency probes alternatives such as pressure and flow recordings together lies around 3-15 Mhz and that wavelength (λ) = propagation with transdiaphragmatic pressure, electromyography and speed / frequency (Mhz) = 1540/15 . 106 = 0.1x10–3 m = 0.1 phrenic nerve stimulation, chest X-ray, fluoroscopy or CT. mm). This might not seem relevant, but 0.1 mm equals 5% of These are: cost-effectiveness, bedside availability, which an average diaphragm with a thickness of 2.0 mm. avoids the necessity for transport to imaging machines, level Furthermore, they found that depending on breath size (above of invasiveness and ease of use. In addition, reference values 50% of inspiratory capacity) tdi% was not correlated with for comparison and evaluation are already existent.[7,12] the volume inhaled. The possible explanation for this is that Consistent monitoring offers useful information about the during inspiration above 50% of one’s inspiratory capacity, diaphragm in ICU patients. Levine et al.[16] showed that as part of the pressure generation is not delivered by diaphragm little as 18-69 hours of ventilation contributed to significant contraction alone, but expansion of the thorax as well. This atrophy of the diaphragm. A different study further quantified leads to the conclusion that ultrasound measurements can be the atrophy by measuring diaphragm thickness with feasible parameters, as long as limitations like these are kept ultrasound, finding a daily 11% decay and a total reduction of in mind. 32% from starting thickness during the first 3 days of MV.[29] Independent of breath size, lung volume seemed to play an Recently, it was found that low contractile activity of the important role in measurements of the diaphragm.[32,33] In diaphragm was associated with rapid decreases in thickness, increasing lung volumes variability of measurements between whereas high contractile activity was associated to increased observers increased as well. This did not seem to be the case thickness.[30] Activity of the diaphragm was directly and for intra-observer variability[34] and indicated that most of the negatively influenced by increasing driving pressures and measurements acquired in a patient should rather be used as controlled ventilator modes. Too high levels of assistance may their own reference value.

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In summary, it can be concluded that diaphragm ultrasound be used, explained how they are obtained and how they can measurements are highly repeatable and reproducible under be applied. Monitoring weaning and predicting extubation standardised conditions and with experienced operators. outcome are key elements. Nevertheless, many of the studies were performed in Limitations selected cohorts and have yet to be evaluated in larger, more While ultrasonography of the diaphragm offers advantages, heterogeneous patient groups. In addition, some of the papers its limitations have to be kept in mind for optimal use and were already published as early as 2001,[13] while others interpretation of results. appeared in 2016,[27] creating a gap of 15 years in which the First of all, it has to be mentioned that while learning how to quality of ultrasound and our understanding of the function use an ultrasound machine is fairly easy, making precise and of the diaphragm has changed significantly. As follows, this reproducible images is less so. One factor, as already pointed provides a vast range of possible research in the future. out, is the limit of resolution inherent to the ultrasound machine Almost all papers evaluated ultrasonography while solely and can therefore not be circumvented. A 5% inaccuracy in looking at the diaphragm, even though multiple organ systems measurements has to be accepted for now and treated with could be analysed at once, to provide a broader perspective caution when basing clinical decisions on ultrasound images. for interpretation of findings. Mayo et al.[35] hypothesised that Another factor is presented by the variability between observers, looking at the diaphragm with ultrasound during weaning which although small and perhaps negligible, is still present. To in combination with taking measurements of the lung and improve this variability placement of the ultrasound probe can heart in the same session might be superior to measuring be standardised by marking the measurement site. However, the diaphragm alone. They concluded that this approach slight tilting and rotation of the probe are sometimes necessary could lead to improvement of weaning outcomes, as heart, for optimal images and hard to prevent and reproduce, causing lungs and diaphragm are closely related in this regard. More an additional inaccuracy. specifically, identification of underlying causes such as left ventricular dysfunction, pleural effusion or inadequate lung Table 4. Applicability of parameters by mode of ventilation aeration could lead to more targeted interventions. Measurement: Mode of ventilation: New techniques such as speckle tracking are emerging and are Spontaneous Assisted Controlled slowly finding their way into clinical practice. It uses naturally occurring speckle patterns to analyse the deformation and Motion + - - motion of tissues. Using this technique, a new parameter Thickness + + + called strain was introduced as a way of quantifying diaphragm TF + + - function. It describes active shortening of a given segment related to the length at a previous time point. D-RSBI + - n.a. Ye et al.[36] used strain measurements in healthy volunteers and Synchrony n.a. + - showed that certain parts of the diaphragm contribute to its force generating capacity in different extents than others. The crura TF: tickening fraction D-RSBI: diaphragmatic rapid shallow breathing index and the part in the zone of apposition displayed roughly equal +: can be used -: can’t be used amounts of strain, while the domes showed significantly smaller values. They thus hypothesised that functionality throughout the Furthermore, ultrasonography of the diaphragm is limited by muscle is not as homogenous as is frequently assumed. ventilatory settings (Table 4). For example, measurements of Hatam et al.[37] investigated strain measurements in healthy diaphragm motion can only be obtained during spontaneous non-invasively ventilated volunteers and found that with breathing, as during assisted ventilation no clear distinction increasing pressure support, diaphragm strain increased as can be made between active contractile and passive ventilator well, indicating the increased work it delivers to resist the pressure driven displacement. During completely controlled driving pressures. These results could indicate that diaphragm modes of ventilation neither motion nor thickness/thickening strain offers a new approach to quantify diaphragm function should be measured for the same reason, even though passive and the work it delivers. motion and thickening can be observed and misinterpreted as muscular activity. Ultrasound contrast agents are also a field of great interest. Small liquid-gas emulsions, surrounded by a shell that Future perspectives prevents leakage and aggregation, called microbubbles, can Ultrasonography of the diaphragm is a rapidly expanding be used to create a strong echogenic response and with that, field with new indications evolving around it. As described highlight and improve visualisation of the tissue of interest. In above, several studies have demonstrated parameters that can addition, these microbubbles can be destroyed purposefully

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[38] 11. DiNino E, Gartman EJ, Sethi JM, McCool FD. Diaphragm ultrasound as a to measure replenishment rates and with it tissue perfusion, predictor of successful extubation from mechanical ventilation. Thorax. or even be made tissue specific by targeting certain proteins 2014;69:423-7. [39] 12. Boussuges A, Gole Y, Blanc P. Diaphragmatic motion studied by M-mode or DNA. Applying these possibilities to the diaphragm and ultrasonography. Chest. 2009;135:391-400. monitoring its perfusion and inflammation could possibly 13. Gerscovich EO, Cronan M, McGahan JP, Jain K, Jones CD, McDonald C. Ultrasonographic evaluation of diaphragmatic motion. J Ultrasound Med. provide important information, as these factors might play a 2001;20:597-604. key role during atrophy. 14. Kantarci F, Mihmanli I, Demirel MK, et al. Normal diaphragmatic motion and the effects of body composition: determination with M-mode sonography. J In summary, with all ongoing research and the implementation Ultrasound Med. 2004;23:255-60. of new US techniques, we think it is only a matter of time 15. Supinski GS , Callahan LA. Diaphragm weakness in mechanically ventilated critically ill patients. Crit Care. 2013;17(3):R120. before ultrasonography evaluation of the diaphragm will 16. Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm become a part of routine clinical practice. fibers in mechanically ventilated humans. New Engl J Med. 2008:358:13-22. doi:10.1056/NEJMoa1505949. 17. Hooijman PE, Beishuizen A, Witt CC, et al. Diaphragm Muscle Fiber Weakness Conclusion and Ubiquitin-Proteasome Activation in Critically Ill Patients. Am J Respir Crit Care Med. 2015;191:1126-38. Ultrasonography is a versatile and easy to use tool for 18. Jaber S, Jung B, Matecki S, Petrof BJ. Clinical review: Ventilator-induced mapping the diaphragm in various clinical settings, with a diaphragmatic dysfunction - human studies confirm animal model findings! Crit Care. 2011;15:206. good reproducibility and repeatability. Diaphragm motion, 19. Mariani LF, Bedel J, Gros A, et al. Ultrasonography for Screening and Follow-Up analysed by using a low frequency probe in M-mode, is used of Diaphragmatic Dysfunction in the ICU: A Pilot Study. J Intensive Care Med. 2015. doi:10.1177/0885066615583639. in independently breathing patients to detect dysfunction, 20. Gilbert R, Auschincloss JH, Peppi D. Relationship of rib cage and abdomen paralysis and ventilator asynchrony. Measurements of motion to diaphragm function during quiet breathing. Chest. 1981;80:607-12. 21. Vivier E, Dessap AM, Dimassi S, et al. Diaphragm ultrasonography to estimate thickness, acquired with a high frequency probe in B-mode, the work of breathing during non-invasive ventilation. Intensive Care Med. can monitor atrophy and calculate the thickening fraction 2012;38:796-803. 22. Umbrello M, Formenti P, Longhi D, et al. Diaphragm ultrasound as indicator which in turn is used to assess muscle function and to predict of respiratory effort in critically ill patients undergoing assisted mechanical the ability to sustain spontaneous breathing after extubation. ventilation: a pilot clinical study. Crit Care. 2015;19:161. 23. Zanforlin A, Bezzi M, Carlucci A, DiMarco F. Clinical applications of diaphragm Limitations are its potential for inaccuracy and restricted use ultrasound: moving forward. Minerva Med. 2014;105:1-5. to certain clinical settings, meaning that during completely 24. DiNino E, Gartman E, Sethi J. Diaphragm ultrasound as a new index of discontinuation from mechanical ventilation. Thorax. 2014;69:431-5. controlled modes of ventilation almost all the currently used 25. Hershenson MB, Kikuchi Y, Tzelepis GE, McCool FD. Preferential fatigue of the rib cage muscles during inspiratory resistive loaded ventilation. J Appl Physiol. ultrasound parameters are not viable and that diaphragm 1989;66:750-4. motion can only be interpreted during spontaneous breathing. 26. Hershenson MB, Kikuchi Y, Loring SH. Relative strengths of the chest wall muscles. J Appl Physiol. 1988;65:852-62. Furthermore, there are currently no studies that demonstrate 27. Farghaly S, Hasan AA. Diaphragm ultrasound as a new method to predict US of diaphragm being a viable diagnostic tool on its own, extubation outcome in mechanically ventilated patients. Aust Crit Care. April 2016. doi:10.1016/j.aucc.2016.03.004. which warrants caution and further research. 28. Spadaro S, Grasso S, Mauri T, et al. Can diaphragmatic ultrasonography performed during the T-tube trial predict weaning failure? The role of References diaphragmatic rapid shallow breathing index. Crit Care. 2016;20. doi:10.1186/ s13054-016-1479-y. 1. Lerolle N, Guérot E, Dimassi S, et al. Ultrasonographic diagnostic criterion for 29. Schepens T, Verbrugghe W, Dams K, Corthouts B, Parizel PM, Jorens PG. The severe diaphragmatic dysfunction after cardiac surgery. Chest. 2009;135:401- course of diaphragm atrophy in ventilated patients assessed with ultrasound: 7. a longitudinal cohort study. Crit Care. 2015;19:422. 2. Kim WY, Suh HJ, Hong S-B, Koh Y, Lim C-M. Diaphragm dysfunction assessed by 30. Goligher EC, Fan E, Herridge MS, et al. Evolution of diaphragm thickness during ultrasonography: Influence on weaning from mechanical ventilation. Crit Care mechanical ventilation: Impact of inspiratory effort. Am J Respir Crit Care Med. Med. 2011;39(12):1. 2015;192:1080-8. 3. Heunks LM, Doorduin J, van der Hoeven JG. Monitoring and preventing 31. Thille AW, Cabello B, Galia F, Lyazidi A, Brochard L. Reduction of patient- diaphragm injury. Curr Opin Crit Care. 2015;21:34-41. ventilator asynchrony by reducing tidal volume during pressure-support 4. Govanni Ferrari GDF, Fabrizio Elia1, Francesco Panero GV and FA. Diaphragm ventilation. Intensive Care Med. 2008;34:1477-86. ultrasound as a new index of discontinuation from mechanical ventilation. 32. ation. J Appl Physiol. 1997;83:291-6. Thorax. 2014;69:431-5. 33. Ueki J, De Bruin PF, Pride NB. In vivo assessment of diaphragm contraction by 5. Wunsch H, Wagner J, Herlim M, Chong DH, Kramer AA, Halpern SD. ICU ultrasound in normal subjects. Thorax. 1995;50:1157-61. occupancy and mechanical ventilator use in the United States. Crit Care Med. 34. Baldwin CE, Paratz JD, Bersten AD. Diaphragm and peripheral muscle thickness 2013;41:2712-9. on ultrasound: Intra-rater reliability and variability of a methodology using 6. Thille AW, Harrois A, Schortgen F, Brun-Buisson C, Brochard L. Outcomes non-standard recumbent positions. Respirology. 2011;16:1136-43. of extubation failure in medical intensive care unit patients. Crit Care Med. 35. Mayo P, Volpicelli G, Lerolle N, Schreiber A, Doelken P, Vieillard-Baron A. 2011;39:1. Ultrasonography evaluation during the weaning process: the heart, the 7. Matamis D, Soilemezi E, Tsagourias M, et al. Sonographic evaluation of diaphragm, the pleura and the lung. Intensive Care Med. 2016;42:1-11. the diaphragm in critically ill patients. Technique and clinical applications. 36. Ye X, Xiao H, Bai W, Liang Y, Chen M, Zhang S. Two-dimensional strain Intensive Care Med. 2013;39:801-10. ultrasound speckle tracking as a novel approach for the evaluation of right 8. Ayoub J, Cohendy R, Dauzat M, et al. Non-invasive quantification of diaphragm hemidiaphragmatic longitudinal deformation. Exp Ther Med. 2013;6:368-72. kinetics using m-mode sonography. Can J Anaesth. 1997;44:739-44. 37. Hatam N., Goetzenich A., Rossaint R., Karfis I., Bickenbach J., Autschbach R., 9. Carrillo-Esper R, Perez-Calatayud AA, Arch-Tirado E, et al. Standardization of Marx G. Bruells C., Ultraschall in Med 2014; 35: 540–546. Sonographic Diaphragm Thickness Evaluations on Healthy Volunteers. Respir 38. Wei K, Jayaweera AR, Firoozan S, Linka A, Skyba DM, Kaul S. Quantification of Care. 2016;(C):1-5. myocardial blood flow with ultrasound-induced destruction of microbubbles 10. Goligher EC, Laghi F, Detsky ME, et al. Measuring diaphragm thickness with administered as a constant venous infusion. Circulation. 1998;97:473-83. ultrasound in mechanically ventilated patients: feasibility, reproducibility and 39. Lindner JR, Song J, Christiansen J, Klibanov AL, Xu F, Ley K. Ultrasound validity. Intensive Care Med. 2015;41:642-9. assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin. Circulation. 2001;104:2107-12.

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The NVIC will award a prize for the best Review and the best Original Article in 2018. In both categories the top 3 papers NJCC in 2018 will be nominated by the executive board of the Netherlands Journal of Critical Care. BEST ARTICLE NVIC members may vote and the prizes will be awarded during the Intensivistendagen in February 2019. OF THE YEAR The executive board invites you to submit your article to the Netherlands AWARD Journal of Critical Care.

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64 NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 Netherlands Journal of Critical Care

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NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 65 Netherlands Journal of Critical Care Submitted October 2017; Accepted November 2017

ORIGINAL ARTICLE

To see or not to see: ultrasound-guided percutaneous tracheostomy

J.E. Lopez Matta, C.V. Elzo Kraemer, D.J. van Westerloo Department of Intensive Care Medicine, Leiden University Medical Centre, Leiden, the Netherlands

Correspondence J. Lopez Matta - [email protected]

Keywords - ultrasound, tracheostomy, percutaneous dilatational tracheostomy, intensive care

Abstract Percutaneous dilatational tracheostomy is a common bedside drawbacks as well. Not only does it increase the number of procedure in an intensive care unit. Historically, a technique people and the skill set needed to perform a PDT but it has using bronchoscopic guidance is used. We describe here a new also been associated with measurable alveolar derecruitment version of this technique in which ultrasound is used to lower accompanied by procedural decreases in oxygen saturation.[3] the chance of vascular damage and ensure proper placement of the cannula in the midline position at the optimal level. In recent years, ultrasound has become much more widely We describe the protocol we use for this intervention at our available in the ICU environment. Ultrasound is increasingly used institution and review the evidence for the feasibility and safety to aid in central line placement and visualise organs such as the of ultrasound-guided percutaneous dilatational tracheostomy. heart and lungs. Increasingly, vital treatment decisions in the ICU setting, such as whether or not patients may be fluid responsive, Introduction are based on intensivist-performed point of care ultrasound. In Percutaneous dilatational tracheostomy (PDT) is a common this short paper, we describe that the use of ultrasound during bedside procedure in an intensive care unit (ICU). Its simplicity, PDT enables clinicians to not only increase the ease and speed of safety profile and lower cost in comparison with a classical a PDT procedure but to increase its safety as well. In this article, surgical tracheostomy has popularised the procedure so that it we will present a brief review of the evidence supporting the use is now the procedure of choice in most units and intensivist- of ultrasound in this procedure and describe the technique we led PDT.[1] Although safe, the PDT procedure is not exempt of currently use at the Leiden University Medical Centre (LUMC). complications such as bleeding, false routes and even death. It has been reported that PDT-related mortality occurs in 1 out Ultrasound-guided PDT of every 600 patients.[2] The vast majority of these PDT-related In preparation for PDT, the patient is sedated, and the head is deaths are due to uncontrollable periprocedural haemorrhage, placed in slight hyperextension in order to expose the neck. usually secondary to unanticipated variations in the vascular In this position, the operator will palpate the neck and locate anatomy in the neck.[2] The implementation of additional safety important landmarks such as the thyroid cartilage, cricothyroid measures is focussed on the prevention of PDT-related bleeding membrane, cricoid and sometimes even the tracheal rings. and is of utmost importance to reduce the rate of complications.[2] This is essential for choosing the correct localisation for the tracheostomy. In certain groups of patients this procedure is Many institutions have implemented the adjunctive use of difficult or even impossible to perform because of factors such bronchoscopic guidance during a PDT as an additional safety as obesity or neck deformations.[4] In all patients but especially measure. This technique enables the confirmation of midline this group ultrasound can play a pivotal role in helping to puncture of the trachea and allows for the visualisation of the distinguish the neck anatomy and still allow the patient to posterior tracheal wall preventing its potential perforation. undergo a PDT without having to opt for the more invasive Although bronchoscopic guidance is of great help to aid in surgical procedure.[5] periprocedural visualisation, it does not prevent the potential The transversal axial view using a high frequency linear probe laceration of unanticipated vascular abnormalities leading to is the most adequate to determine whether the puncture haemorrhage. Additionally, bronchoscopy during PDT has its is actually in the midline and to avoid the thyroid gland.

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Furthermore, the transversal axial view is used to determine needle in the midline of the trachea by following the acoustic the presence of vasculature in the pre-tracheal or para-tracheal shadow ahead of the needle, followed by the displacement of the regions which might be vulnerable to laceration during the tissue layers observed with the needle passage, allowing correct procedure. If present, a lower or higher puncture location can positioning and avoidance of vascular structures. Intraluminal be chosen. The longitudinal view has the advantage of giving air prevents the visualisation of structures such as the posterior the operator a ‘birds-eye’ view of the neck anatomy and the pharynx and posterior wall of the trachea; therefore, injury at relationship between the different structures. This is the best this level cannot be fully avoided using ultrasound alone. Also, view when choosing the level of the tracheal puncture. Most a drawback of the procedure is that the guidewire cannot be authors agree that the point of tracheal puncture should be seen in the trachea. However, its penetration between the below the first tracheal ring but above the fourth tracheal ring. tracheal ring can be observed in a longitudinal axis view and a The exact location depends on patient (e.g. vascular) anatomy. subcutaneous positioning can be discarded. Having said that, we believe that the puncture should not be too Using ultrasound during PDT leads to the potential to avoid low; preferably try to insert the tracheal cannula between the vascular structures, perfect midline puncture as well as control second and third inter-tracheal membranes. of intraluminal positioning of the guidewire which largely excludes the necessity of using bronchoscopy for this procedure. The pre-tracheal and para-tracheal space can be visualised with the help of ultrasound. Anatomically it allows to identify Ultrasound-guided PDT protocol the cervical vasculature,[6] helps to identify the ideal tracheal The patient who has previously fasted for at least five hours puncture site,[7] and helps to calculate the distance from skin to is sedated and adequately positioned with hyperextension of trachea, which in turn allows for the selection of an appropriately the neck. The ultrasound machine is placed at the opposite sized tracheostomy tube.[8] This is done preferably with a linear side of the operator. An ultrasound is performed of the neck high frequency probe either in longitudinal sections or transverse in transversal and longitudinal view (figure 1). Cricoid cartilage sections (figure 1). The cricoid cartilage (figure 1A) can be and tracheal rings are identified, as well as pre-tracheal and easily recognised just inferior to the cricothyroid membrane para-tracheal regions of the neck searching for unexpected by its relatively large acoustic shadow, followed caudally by abnormal vasculature. the tracheal rings (figure 1B). These cartilaginous structures A sterile field is prepared around the operation site and the appear hypoechoic on ultrasound due to their relatively high linear probe is used. water content. Transversally they resemble an inverted ‘U’ and The skin and subcutaneous tissue in the operation zone is longitudinally these can be identified as round-like hypoechoic infiltrated with local anaesthetics with adrenalin, which has structures forming a ‘string of beads’. The anterior surface of the two functions. The first is vasoconstriction of subcutaneous trachea is delineated by a bright air-mucosal interface (figure capillaries/vessels and the second is increasing the resolution of 1C) and by reverberation artefacts from intraluminal air. the neck landmarks by placing a depot of liquid which enhances the image quality beneath. Real-time ultrasound guided PDT is the use of ultrasound At this point the endotracheal tube is retrieved to just above the during the procedure itself. In their review, Alansari et vocal cords under visualisation with the use of the laryngoscope. al.[9] describe that the midline for the tracheal puncture is This is only done if the patient has high ventilator support determined in a transversal axis. The puncture is performed parameters, arbitrarily a PEEP level >8 or high delta pressures. with US guidance in real time observing the penetration of the If ventilator parameters are low, which is almost always the case, we usually replace the endotracheal tube with a laryngeal mask since we feel that keeping the tube to facilitate the use of a bronchoscope is not necessary when using this ultrasound- guided technique. Having said that, bronchoscopy through a laryngeal mask is still feasible if needed.

The preferred tracheal ring space is chosen with the longitudinal ultrasonographic view (figure 1). As mentioned earlier this one is located anywhere between tracheal ring 1 and 4. The blue dilatator of the tracheostomy set is used to identify this localisation by pressing lightly on the skin and observing with the ultrasound at which tracheal ring level the pre-tracheal tissue is being pressed (figure 2A). This ‘mark’ is used as a Figure 1. guide and the linear probe is placed transversally at this level.

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The tracheal ring just beneath the tracheal ring space chosen is visualised. The midline of the desired tracheal puncture localisation is placed in the middle of the ultrasound screen, and the puncture needle (coupled to a 5 or 10 ml saline-filled syringe) is introduced perpendicularly to the skin and advanced until the needle is seen to pass the anterior tracheal wall with aspiration of air (figure 1B and C). Once this has been achieved, the ultrasound linear probe is discarded. At this point the needle is angled caudally, and is retrieved leaving the plastic catheter behind. The guidewire is then introduced and once intraluminal placement is confirmed the plastic catheter is removed leaving the guidewire in the trachea (figure 2D). A small horizontal or vertical incision (depending if nearby vessels are observed) Figure 2. is made at each side of the guidewire to allow dilatation. The puncture site is sequentially dilated using the small dilator up as a non-inferiority study comparing US-PDT and B-PDT.[7] first followed by the bigger green dilator (figure 2E). Once The results showed that US-PDT was equally fast and safe to introduced until the pre-specified marker on the dilator, it is left B-PDT. There were no major complications in the two groups. in situ for 1 minute as specified by its manufacturer (figure 2F). Minor complications were slightly more frequent in the US-PDT The dilator is then removed leaving the guidewire behind. The group but this was not statistically significant (33.3% vs 22.7%). trachea cannula is introduced using the guidewire and once in Finally, in a retrospective study involving 200 patients the use place the latter is removed and the inner cannula is introduced of ultrasound during PDT was associated with a significantly followed by connection to the ventilator. lower rate of procedure-related complications in a propensity [14] Correct placement is controlled by the presence of end tidal CO2 score matched analysis. The use of ultrasound speeds up the and/or with the use of the linear probe to confirm the presence procedure considerably since the median time between puncture of ‘lung-sliding’ bilaterally and/or a ‘seas shore sign’ on M mode and guidewire insertion has been reported to be around 12 (figure 2G) which confirms bilateral ventilation. seconds whereas completion of the entire procedure only takes about 12 minutes.[15] Other authors have reported even faster Discussion average times of up to 8 minutes for the full procedure, which in Ultrasound technology is rapidly advancing, ranging from bulky the study of Sustic et al.[16] was significantly faster when compared machines to ultraportable pocket sized equipment.[10]. This with surgical tracheostomy, which took an average of 12 minutes. progressive innovation and decrease in costs has brought the ultrasound outside the radiology departments directly to the Every new procedure has a learning curve. At our centre we bedside. With regards to the evidence for the use of ultrasound have not yet reached agreement as to the number of US-PDT during PDT, four randomised controlled trials have compared procedures that must be correctly performed to be considered ultrasound-guided PDT (US-PDT) with bronchoscopic guided proficient. Our staff and fellows use ultrasound daily, which PDT(B-PDT).[7,11-13] Yavuz et al. randomised 341 patients to helps. We feel that the procedure is not very difficult for US-PDT or PDT only guided by landmarks and showed that physicians with ultrasound experience and experience with in the US-PDT group, the puncture site designated before the previous techniques and we expect the average learning curve to ultrasound analysis was reconsidered in 23.8% of the cases.[12] be between 10-20 procedures. However, given the fact that not Complication rates were lower in the US-PDT group although many PDT procedures are carried out each month, departments not statistically significantly, reflecting the general relative might consider restricting the technique initially to certain safety of the procedure. A study in 74 patients compared, among staff members to allow them to build up some experience. To other endpoints, the ease of the procedure as well as the rate of facilitate training, we are busy setting up a ‘dummy’ in which complications between US-PDT and B-PDT. In line with other this technique can be practised on by other staff members as reports the procedure was significantly shorter in the US-PDT well as fellows. group when compared with the B-PDT group (14 vs 18 min).[13] Taken together, the results of the randomised controlled trials In terms of complications, 8 tracheal cuff punctures (22.2%) which have been performed in this field show no inferiority but were observed in the B-PDT group and zero cuff punctures also no clear preference for the use of US-PDT. Although clear in the US-PDT group (p < 0.05). Whereas all US-PDT guided significant benefits from a US-PDT technique are not shown procedures only needed one tracheal puncture in the B-PDT in the literature one should bear in mind that the complication group several punctures were needed in some patients. A recent rates of this procedure are very low and that the number of randomised controlled trial with a total of 118 patients was set included patients in all studies was too low to be able to show

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5. Guinot PG, Zogheib E, Petiot S, et al. Ultrasound-guided percutaneous any significant benefit. However, we feel that the benefits of tracheostomy in critically ill obese patients. Crit Care. 2012;16:R40. this technique are quite important. First of all, the technique 6. Flint AC, Midde R, Rao VA, Lasman TE, Ho PT. Bedside ultrasound screening for pretracheal vascular structures may minimize the risks of percutaneous adds a layer of safety to the procedure since vascular structures dilatational tracheostomy. Neurocrit Care. 2009;11:372-6. in the neck are clearly visualised. Second the technique does 7. Gobatto AL, Besen BA, Tierno PF, et al. Ultrasound-guided percutaneous dilatational tracheostomy versus bronchoscopy-guided percutaneous not require the use and availability of a bronchoscope which dilatational tracheostomy in critically ill patients (TRACHUS): a randomized significantly increases flexibility and reduces preparatory time. noninferiority controlled trial. Intensive Care Med. 2016;42:342-51. 8. Garg R, Gupta A. Ultrasound: A promising tool for contemporary airway Also, since a continuously patent airway (e.g. a tube) is not management. World J Clin Cases. 2015;3:926-9. required, one may opt to replace the tube by a laryngeal mask 9. Alansari M, Alotair H, Al Aseri Z, Elhoseny MA. Use of ultrasound guidance to improve the safety of percutaneous dilatational tracheostomy: a literature before the procedure, which significantly decreases the time review. Crit Care. 2015;19:229. and effort needed for airway handling. Finally, since airway and 10. S.Islam HT. Thoracic Ultrasound Overview. In: C.T. Bolliger, editor. Clinical Chest Ultrasound: From the ICU to the Bronchscopy Suite. Clinical Chest Ultrasound: bronchoscope handling are omitted the procedure may easily be From the ICU to the Bronchscopy Suite 37. Basel, Switzerland: Karger; 2009. p. performed by a single operator. 11-20. 11. Rudas M, Seppelt I, Herkes R, Hislop R, Rajbhandari D, Weisbrodt L. Traditional landmark versus ultrasound guided tracheal puncture during percutaneous Disclosures dilatational tracheostomy in adult intensive care patients: a randomised controlled trial. Crit Care. 2014;18:514. All authors declare no conflict of interest. No funding or 12. Yavuz A, Yilmaz M, Goya C, Alimoglu E, Kabaalioglu A. Advantages of US in financial support was received. percutaneous dilatational tracheostomy: randomized controlled trial and review of the literature. Radiology. 2014;273:927-36. 13. Ravi PR, Vijay MN. Real time ultrasound-guided percutaneous tracheostomy: References Is it a better option than bronchoscopic guided percutaneous tracheostomy? Medical journal, Armed Forces India. 2015;71:158-64. 1. Sangwan YS, Chasse R. A modified technique for percutaneous dilatational 14. Rajajee V, Williamson CA, West BT. Impact of real-time ultrasound guidance on tracheostomy: A retrospective review of 60 cases. J Crit Care. 2016;31:144-9. complications of percutaneous dilatational tracheostomy: a propensity score 2. McCormick B, Manara AR. Mortality from percutaneous dilatational tracheostomy. analysis. Crit Care. 2015;19:198. A report of three cases. Anaesthesia. 2005;60:490-5. 15. Chacko J, Gagan B, Kumar U, Mundlapudi B. Real-time ultrasound guided 3. Mehta C, Mehta Y. Percutaneous tracheostomy. Ann Card Anaesth. percutaneous dilatational tracheostomy with and without bronchoscopic 2017;20(Supplement):S19-s25. control: an observational study. Minerva Anestesiol. 2015;81:166-74. 4. Husein OF, Massick DD. Cricoid palpability as a selection criterion for bedside 16. Sustic A, Krstulovic B, Eskinja N, Zelic M, Ledic D, Turina D. Surgical tracheostomy tracheostomy. Otolaryngology--head and neck surgery : official journal of versus percutaneous dilational tracheostomy in patients with anterior cervical American Academy of Otolaryngol Head Neck Surg. 2005;133:839-44. spine fixation: preliminary report. Spine. 2002;27:1942-5; discussion 5.

NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 69 Netherlands Journal of Critical Care Submitted: April 2017; Accepted: June 2017

CASE REPORT

Pneumatosis intestinalis, to treat or not to treat?

N. Treskes1, B. Festen-Spanjer2 1Department of Intensive Care & Anaesthesiology, St Antonius Hospital, Nieuwegein, the Netherlands 2Department of Intensive Care Medicine, Gelderse Vallei Hospital, Ede, the Netherlands.

Correspondence N. Treskes - [email protected]

Keywords - pneumatosis intestinalis, acute intestinal ischaemia, portal venous gas, pulmonary embolism

Abstract contrast of the thorax and abdomen detected two embolisms: We present the case of an 81-year-old patient who was admitted a longitudinal embolism reaching from the superior to the to the intensive care unit of our hospital with severe septic inferior mesenteric artery and a second embolism located in the shock due to acute mesenteric ischaemia and pulmonary artery pulmonary truncus and right pulmonary artery (figure 1). Severe embolism. This case has several diagnostic, therapeutic and pneumatosis intestinalis of both the colonic and intestinal wall prognostic dilemmas. The diagnostic and prognostic accuracy and additionally portal venous gas were present. The patient of pneumatosis intestinalis and portal venous gas are discussed. was taken to the operating room. A thrombectomy of the longitudinal thrombus was performed and simultaneously 350 Background cm of necrotic small bowel was resected. Acute mesenteric ischaemia (AMI) is a severe medical condition Postoperatively, the patient was treated in the intensive care with a mortality rate up to 50-69%.[1] Untreated, it will cause unit for septic shock with antibiotics, fluids, vasopressors, intestinal necrosis and an excessive inflammatory response inotropes and corticosteroids. Low-molecular-weight heparin leading to multi-organ failure and death. Early intervention is was started because of the pulmonary embolism. The next pivotal for a chance of survival. However, diagnosis is difficult, day, a second-look laparotomy was performed, resulting in especially in the early stages when intervention is most the removal of the necrotic caecum and gallbladder. After beneficial. the second operation the patient deteriorated rapidly with combined septic and cardiogenic shock. Cardiac ultrasound Case presentation showed right atrial overload, an open foramen ovale was not An 81-year-old man, with a history of type II diabetes mellitus, observed. Thrombolysis for the pulmonary embolism was hypertension, dyslipidaemia and mild proteinuria, presented to contraindicated because of recent surgery. The patient was the emergency department with progressive abdominal pain considered too unstable for thrombectomy. Further medical existing for several hours. He reported fever and vomiting. treatment was regarded as futile and palliative care was The patient was pale, disorientated, tachycardic (97/min), started. The patient died in the presence of his family. Autopsy tachypnoeic (24/min) and hypoxic (SaO2 90% in room air). was performed and revealed a recent pulmonary embolism, Further physical examination revealed signs of peritonitis. severe atherosclerosis of the aorta and the coronary arteries, Arterial blood gas analysis showed hypoxaemia and a respiratory cardiac hypertrophy, and a shock aspect of the liver, spleen and compensated metabolic acidosis with increased lactate level (pH pancreas. Neither macroscopic nor microscopic examination 7.38; PaCO2 4.0 kPa; PaO2 7.4 kPa; HCO3 16.2 mmol/l; lactate revealed malignancy. 3.9 mmol/l). Furthermore, he had renal insufficiency (creatinine 206 µmol/l, previously 150 µmol/l), leukocytosis (20.7 x 109/l) Discussion and an increased CRP (41 mg/l). A chest X-ray showed perihilar In Europe and the USA, AMI accounts for about 1:1000 oedema, an electrocardiogram showed sinus rhythm and right hospital admissions.[1] It is an abdominal emergency requiring bundle branch block. rapid diagnosis and treatment. Diagnosis, however, is difficult, During the diagnostic work-up, the patient’s condition due to non-specific clinical signs and lack of non-invasive deteriorated. A computed tomography (CT) with intravenous diagnostic tests. Despite a decline in mortality rates over

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the past 50 years, they remain high at 50-69%[1]. AMI may findings. A number of factors are associated with increased be provoked by various mechanisms and has different risk mortality, including advanced age, admission from a nursing factors. Consequently, there are different diagnostic methods home, partial dependence, coma, artificial ventilation, chronic and therapeutic options. Obstructive AMI can be caused by obstructive pulmonary disease and recent (<6 months) bowel strangulation or volvulus.[1-3] Four aetiological forms of myocardial infarction. Also, presentation >24 hours after vascular AMI have been identified: arterial embolism (EAMI), the onset of symptoms and signs of peritonitis, organ failure, arterial thrombosis (TAMI), venous thrombosis (VAMI) and and sepsis, are independent risk factors for mortality.[4] So, non-occlusive mesenteric ischaemia (NOMI).[4] EAMI accounts according to the European Society for Trauma and Emergency for 45% of causes of AMI and is associated with comorbidities Surgery guidelines on AMI, the decision to either proceed to that predispose to formation of arterial thrombi, such as atrial curative treatment or palliative care should be based on the full fibrillation.[5] A sudden onset of pain, with prompt emptying history and pre-hospital performance status, clinical and lab of the bowel, without specific physical symptoms is a classical findings. However, the guidelines are unclear about the value sign of EAMI. In approximately 25% of the cases, arterial of radiological findings in this decision-making process. With thrombosis is the underlying mechanism of AMI. Risk factors this in mind we endeavoured to assess the prognostic accuracy include atherosclerotic disease and dyslipidaemia. Patients of CT findings. present with prodromal abdominal angina.[6] Patients with hypercoagulable states are prone to venous thrombosis. Venous Prognostic predictive value of pneumatosis intestinalis occlusion is usually peripheral, involving different ischaemic Pneumatosis intestinalis is defined as the presence of gas in the bowel segments. The presentation is subacute and can take up submucosa or subserosa of the intestinal wall. In some cases, to two weeks of abdominal pain, nausea and vomiting. NOMI pneumatosis intestinalis is an incidental finding associated may be caused by profound and disproportionate splanchnic with a benign aetiology, and patients can be observed without vasoconstriction during low flow states in critically ill patients. intervention. In others, it is a symptom of a life-threatening Alternatively, it can occur perioperatively during major aortic disease and urgent surgical resection of ischaemic bowel is surgery when splanchnic blood flow is disrupted or mesenteric required. The pathophysiology of this clinically challenging arteries are sacrificed.[7,8] phenomenon is still poorly understood. Theoretically, it can be caused by intraluminal pressure and gas producing bacteria. Diagnosis of acute mesenteric ischaemia Raised intraluminal pressure, for example due to obstruction, Early diagnosis is crucial for reversal of ischaemic damage. causes mechanical injury to the intestinal wall, which allows Delayed intervention may result in intestinal necrosis, multiple gas migration into the submucosal or subserosal layer.[11] In case organ dysfunction syndrome, and death. However, diagnosis is of increased intrathoracic pressure, air leakage from alveolar difficult, particularly in the early stages when treatment is most rupture in pulmonary diseases migrates to the retroperitoneum beneficial. The accuracy of the currently available laboratory through the mediastinum and locates within the bowel tests (sensitivity and specificity of l-lactate is 86% and 44%, mesentery.[12] Also, pneumatosis intestinalis has been reported white blood count 80% and 50%, and d-dimer 89% and 40%, in patients taking α-glucosidase inhibitors. The increased respectively) is suboptimal for routine clinical use.[9,10] The production of intraluminal air in patients taking these drugs best diagnostic test apart from diagnostic laparotomy remains is attributed to the fermentation of undigested carbohydrates contrast CT (angiography) (sensitivity 94%, specificity 95%).[9] by intestinal bacteria.[13] When intramural gas enters the This is, however, time-consuming, costly, invasive and requires mesenteric veins, air can migrate to the portal venous system. expertise. Several new serological markers may facilitate This is defined as portal venous gas. diagnostic accuracy. Intestinal fatty acid-binding protein, Clinically, the presence of pneumatosis intestinalis has always ischaemia modified albumin and α- glutathione S-transferase been considered an alarming radiological feature, due to its report a sensitivity of 79%, 95% and 68%, respectively, and a association with advanced mesenteric ischaemia and poor specificity of 91%, 86% and 84%, respectively.[10] Citrulline is outcome.[14,15] Since the widespread use of the CT, the detection of a promising marker as well with a high reported specificity pneumatosis intestinalis and portal venous gas has significantly (100%).[10] Further research is required to identify optimal improved in the last decade. However, these findings are not diagnostic accuracy and clinical utility. always predictive of poor outcome. DuBose et al. evaluated 500 patients with pneumatosis intestinalis and/or portal venous gas Prognosis at presentation in a retrospective multicentre study, and reported an incidence Patients with significant comorbidities and poor performance of ischaemic pneumatosis intestinalis of only 40%.[16] In a status are unlikely to benefit from intervention. When the separate retrospective review of 149 emergency patients with patient is seriously ill but not moribund it is more difficult pneumatosis intestinalis, intestinal ischaemia was diagnosed in to predict prognosis at presentation based only on clinical 54% of the cases. Ischaemia was significantly related to mortality.

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The overall mortality was 42% and the mortality of patients with the prognostic accuracy of pneumatosis intestinalis on CT for ischaemic pneumatosis intestinalis was 53%.[17] Higashizono et AMI. al., reported an incidence of bowel necrosis of 33% in a case Pneumatosis intestinalis is associated with AMI in 33-54% of series of 52 patients with pneumatosis intestinalis and/or portal the cases and has a mortality of 53 - 59%. Some distinctions can venous gas. Overall in-hospital mortality was 23%, whereas 59% be made regarding mortality, namely the number of affected of patients with bowel necrosis died.[18] bowel segments, the pattern of pneumatosis intestinalis and the presence of portal venous gas in combination with pneumatosis It has been questioned whether anatomical location and intestinalis. When pneumatosis intestinalis spreads to two or extension of intraluminal and portal venous gas predicts more bowel segments, is distributed in a band-like pattern or is incidence, severity, and mortality of AMI. On CT scans of combined with portal venous gas, incidence of bowel infarction 23 patients with AMI, mortality increased gradually with the is increased to up to 80%, 88% or 91%, respectively. number of bowel segments involved: 14% for a single segment, up to 80% for two or three infarcted bowel segments.[19] Disclosures Bowel necrosis is suggested to be related to the distribution All authors declare no conflict of interest. No funding or of pneumatosis intestinalis, which can present as particles or financial support was received. air bubbles, referred to as a ‘bubble-like’ pattern. When the amount of air increases, it seems likely that air bubbles could Acknowledgements merge together to form a ‘band-like’ pattern. Reports on the We would like to thank A. van Die, MD, and H.W. Wiersma, distribution of pneumatosis intestinalis have been conflicting. MD, who provided radiological images. Higashizono et al. found no significant difference in distribution between patients with and without bowel necrosis.[18] Wiesner and colleagues reported an incidence of bowel necrosis of 70% for bubble-like pneumatosis and 88% for band-like pneumatosis. However, the association was nonsignificant.[19] As the amount of gas increases, portal venous gas generally expands from the left lobe of the liver to the right anterior and right posterior lobe. Treyaud et al. did not find a significant correlation for portal gas distribution with underlying ischaemia. Similarly, neither the anatomical location of pneumatosis intestinalis (small bowel, large bowel or both), nor the length of intestinal involvement was correlated to mesenteric ischaemia. However, the combination of pneumatosis intestinalis and portal venous gas was significantly associated with underlying ischaemia.[17] As for Wiesner’s population, 91% of the patients with both pneumatosis intestinalis and portal venous gas had transmural bowel infarction, compared with 81% of those with Figure 1. CT angiography of our patient showing: 1) a longitudinal portal venous gas only. Mortality for patients with transmural thrombus from the superior to the inferior mesenteric artery, 2) pneumatosis intestinalis and 3) gas in the mesenteric veins bowel infarction was 53%.[19]

Further considerations References One could argue that our 81-year-old patient with a history 1. Reilly PM, Wilkins KB, Fuh KC, Haglund U, Bulkley GB. The mesenteric hemodynamic of diabetes, hypertension and dyslipidaemia should not have response to circulatory shock: an overview. Shock. 2001;15:329-43. 2. Trompeter M, Brazda T, Remy CT , Vestring T, Reimer P. Non-occlusive undergone surgery. However, the patient was a non-smoker, mesenteric ischemia: etiology, diagnosis, and interventional therapy. Eur Radiol. mobile, self-supporting and the abdominal pain had existed 2002;12:1179-87. 3. Acosta S. Mesenteric ischemia. Curr Opin Crit Care. 2015;21:171-8. for several hours. During diagnostic work-up, the pulmonary 4. Tilsed JVT, Casamassima A, Kurihara H, et al. ESTES guidelines: acute mesenteric embolism seemed of no significant haemodynamic importance, ischaemia. Eur J Trauma Emerg Surg. 2016;42:253-70. 5. Sreedharan S, Tan YM, Tan SG, Soo KC, Wong WK. Clinical spectrum and surgical therefore the decision for surgical intervention was made. management of acute mesenteric ischaemia in Singapore. Singapore Med J. 2007;48:319-23. 6. Gupta N, Schwenk A, Borgstein R. Acute mesenteric ischaemia on enhanced Conclusion computer-tomography. J Radiol Case Rep. 2010;4:24-30 We present a case with severe AMI with pneumatosis intestinalis 7. Ceppa EP, Fuh KC, Bulkley GB. Mesenteric hemodynamic response to circulatory shock. Curr Opin Crit Care. 2003;9:127-32. and presence of portal venous gas on CT scan and have reviewed

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8. De Backer D, Creteur J, Silva E , Vincent JL. Effects of dopamine, norepinephrine, 14. Liebman PR, Patten MT, Manny J, Benfield JR, Hechtman HB. Hepatic-portal and epinephrine on the splanchnic circulation in septic shock: which is best? Crit venous gas in adults: etiology, pathophysiology and clinical significance. Ann Care Med. 2003;31:1659-67. Surg 1978;187:281-7 9. Cudnik MT, Darbha S, Jones J, Macedo J, Stockton SW, Hiestand BC. The diagnosis 15. Griffiths DM, Gough MH. Gas in the hepatic portal veins. Br J Surg 1986;73:172-6 of acute mesenteric ischemia: A systematic review and meta-analysis. Acad 16. DuBose JJ, Lissauer M, Maung AA, et al., for the AST Pneumatosis Study Group. Emerg Med. 2013;20:1087-100. Pneumatosis Intestinalis Predictive Evaluation Study (PIPES): a multicenter 10. Treskes N, Persoon AM, van Zanten ARH. Diagnostic accuracy of novel serological epidemiologic study of the Eastern Association for the Surgery of Trauma. biomarkers to detect acute mesenteric ischemia: a systematic review and meta- Trauma Acute Care Surg. 2013;75:15-23. analysis. Intern Emerg Med (2017). doi:10.1007/s11739-017-1668-y 17. Treyaud MO, Duran R, Zins M, Knebel JF, Meuli RA, Schmidt S. Clinical significance 11. Tsujimoto T, Shioyama E, Moriya K, et al.Pneumatosis cystoides intestinalis of pneumatosis intestinalis - correlation of MDCT-findings with treatment and following alpha-glucosidase inhibitor treatment: a case report and review of the outcome. Eur Radiol. 2017;27:70-9. literature. World J Gastroenterol. 2008;14:6087-92. 18. Higashizono K, Yano H, Miyake O, et al. Postoperative pneumatosis intestinalis 12. Lida A, Naito H, Tsukahara K, et al. Pneumatosis cystoides intestinalis presenting and portal venous gas may indicate bowel necrosis: a 52-case study. BMC as pneumoperitoneum in a patient with chronic obstructive pulmonary disease: Surgery. 2016;16:42 a case report. J Med Case Rep. 2017;11:55. 19. Wiesner W, Mortelé KJ, Glickman JN, Ji H, Ros PR. Pneumatosis intestinalis and 13. Hisamoto A, Mizushima T, Sato K, et al. Pneumatosis cystoides intestinalis after portomesenteric venous gas in intestinal ischemia: correlation of CT findings with alpha-glucosidase inhibitor treatment in a patient with interstitial pneumonitis. severity of ischemia and clinical outcome. AJR Am J Roentgenol. 2001;177:1319-23. Intern Med. 2006;45:73-6.

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NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 73 Netherlands Journal of Critical Care Submitted August 2017; Accepted September 2017

CASE REPORT

Bilateral vocal cord palsy: An uncommon late complication of cortical ischaemic stroke

V. Jain, V. Jain, H. Sapra Department of Neuro Anaesthesia & Neuro Critical Care, Medanta The Medicity, Gurgaon, Haryana, India

Correspondence V. [email protected]

Keywords - acute ischaemic stroke, vocal cord palsy, vagus nerve, stroke

Abstract Vocal cord palsy in stroke patients is an uncommon of the right upper and lower limb with slurring of speech. The manifestation and occurs when an area of the cerebral cortex or patient had no lifestyle comorbidities. Non-contrast CT and CT brainstem suppling the recurrent laryngeal nerve branch of the perfusion of brain (activated as per stroke protocol) showed early vagus is damaged. A stroke which affects the motor cortex does ischaemic changes in the left MCA territory and hypodensity in not usually cause paresis of the vocal cords as the vagus nerve the left insular cortex was noted. CT angiography of the brain nucleus is innervated by the corticobulbar tract from both and neck vessels showed that the left MCA was occluded at the sides of the brain. We present a unique case of sudden onset proximal M1 segment. The left bulbar internal carotid artery of bilateral vocal cord palsy due to left fronto-parieto-insular showed luminal thrombus. stroke presenting on the eighth day of ictus. Because the patient presented outside the time window Background for intravenous thrombolysis, he underwent intra-arterial Middle cerebral artery (MCA) stroke describes the sudden onset recanalisation via mechanical thrombectomy. The clot was of a focal neurological deficit resulting from brain infarction or crossed using a Rebar-18 microcatheter and Traxcess micro ischaemia in the territory supplied by the MCA. The MCA is by guidewire, good distal flow was confirmed and two passes far the largest cerebral artery and is the vessel most commonly were done using a Solitare stent. At the end of the procedure, affected by a cerebrovascular accident. The MCA supplies recanalisation was achieved. No complications occurred during most of the outer convex surface of the brain, nearly all the the procedure and post-procedure CT showed no intracerebral basal ganglia, and the posterior and anterior internal capsules. haemorrhage. However, post thrombectomy, there was little Infarcts that occur within the vast distribution of this vessel lead neurological improvement. He was conscious but globally to diverse neurological sequelae. aphasic and power continued to be 0/5 in right upper limb and Primary dysfunction of the larynx following stroke is most 1/5 in lower limb. frequently the result of an insult to the nucleus ambiguus and the nucleus solitarius; however, some authors have described Non-contrast CT brain 2 days later showed an acute infarct insults to the cortical and subcortical pathways that result in loss with slight haemorrhage in the left middle and inferior frontal of the laryngeal cough reflex.[1] One of the most common causes gyrus and in the subjacent white matter, insula and peri-insula of bilateral vocal cord palsy is recurrent laryngeal nerve damage frontotemporal region and ipsilateral basal ganglia; mass effect from thyroid surgery or compression by a tumour. Brainstem was evident in the form of effacement of the adjacent cortical strokes and cortical strokes are rare causes of bilateral and/or sulci and compression of the ipsilateral lateral ventricle. A unilateral vocal paralysis as the solitary nucleus of the vagus midline shift of 7 mm was seen, which had increased by 2 mm nerve is innervated from the corticobulbar tracts from both compared with the previous scan. sides of the brain. With regular physiotherapy, the patient gradually improved Case presentation neurologically. His global aphasia improved to incomprehensible We present the case of a 67-year-old male with complaints of sounds and power improved to 2/5 in right upper limb and 3/5 sudden transient loss of consciousness followed by weakness in lower limb. He remained fully conscious and alert. Non-

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contrast CT brain on day 5 showed a mild interval decrease in in the reticular formation in the lateral medulla at the lower the midline shift from 7 mm (2nd day of admission) to 5 mm. end of the brainstem, it passes between the inferior cerebellar peduncle and olive on the lateral aspect of medulla and descends On day 8, the patient developed intermittent stridor with through the jugular foramen to enter the neck. Further down noisy breathing and was again aphasic. His power, however, the fibres divide and innervate the cricothyroid muscle as the was preserved and repeat CT brain (along with CT perfusion superior laryngeal nerve and recurrent laryngeal nerve from the as part of the stroke protocol) showed no fresh ischaemic ipsilateral vagus.[4] Vocal cord palsy in patients with a cortical changes (figure 1). As the respiratory distress worsened, despite stroke is an unexpected finding as the lesion lies above the nebulisation and steroids, the patient was started on high flow nucleus ambiguus. Our patient had a left fronto-parieto-insular oxygen therapy. He maintained a saturation of 100%, the PaCO2 stroke and developed bilateral vocal cord palsy on the 8th day. was 32, with a respiratory rate of 25-28 breaths per minute but The insular cortex is a portion of the cerebral cortex folded within the breathing was noisy with stridor. The ear, nose and throat the lateral sulcus, separating the temporal lobe from the parietal and team was consulted. On flexible fibre-optic laryngoscopy frontal lobes. Insular stroke is usually associated with an increase examination, bilateral abductor palsy was detected. The patient in levels of metanephrine and sympathetic hyperactivation due to was immediately taken up for emergency surgical tracheostomy. decreased vagus nerve activity; Walter et al. proposed a connection By the next day, the patient’s breathing had improved. He was between the vagus nerve and insular cortex.[5] transferred to the ward on day 11. Swallowing assessment showed no immediate aspiration so the nasogastric tube was Venketasubramanian et al. found vocal cord palsy in 16.6% of removed on day 13. the patients who had a stroke in the cortical or large subcortical areas.[6] However, in their study, vocal cord palsy developed CT brain, repeated on day 15, revealed interval reduction in the within 48 hours of presentation in all patients and none had left MCA infarct and haemorrhagic transformation and patient bilateral vocal cord palsy. They questioned whether the nucleus was discharged home with a tracheostomy tube in situ. ambiguus had bilateral cortical innervation, as was seen in other Follow-up at one month after discharge showed persistent vocal previous studies, meaning that involvement of the nucleus cord palsy and decannulation was deferred as he did not pass ambiguus in stroke may result in unilateral or bilateral vocal the swallowing assessment. cord palsy. Shaw also believed the hypothesis that bilateral innervation of the nucleus ambiguus may not be seen in all individuals.[3]

Nasrat et al.[7] presented a similar case of bilateral vocal cord paralysis due to right insular stroke but the presentation was on the 5th day and the cause was also unknown. They indicated the possibility of a dominant vocal cord centre in this area to be affected by the stroke with a bilateral paralysis presentation.

Conclusion To summarise, with this case report we would like to highlight two points. Firstly, in selected patients there can be a dominant unilateral cortical projection to the bilateral nucleus ambiguus. Secondly, sudden bilateral vocal cord palsy, a potentially life- threatening situation, can present even at >1 week of ictus with an improving clinical and radiological condition of the patient. Figure 1. CT brain on day 8 The cause of delayed presentation remains unclear. Since the morbidity and mortality associated with this condition is high, Discussion all patients with acute ischaemic stroke with dysphonia should Vocal cord palsy means the vocal cord lies in an immobile be regularly screened to rule out vocal cord palsy. position and may cause dysphonia. Bilateral vocal cord palsy may lead to failure to adequately protect the airway and in turn Disclosure there is a risk of regurgitation of gastric contents into the lower Informed written consent was obtained from the patient’s son airway and lungs leading to aspiration pneumonia; this may for publication of this case report. become life threatening secondary to upper airway obstruction.[2,3] The authors declare no conflict of interest. No funding or The vagus nerve originates in the nucleus ambiguus, situated financial support was received.

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References

1. Addington WR, Stephens RE, Widdicombe JG, Rekab K. Effect of stroke location 5. Walter U, Kolbaske S, Patejdl R, Steinhagen V, Abu-Mugheisib M, Grossmann on the laryngeal cough reflex and pneumonia risk. Cough. 2005;1:4. A. Insular stroke is associated with acute sympathetic hyperactivation and 2. Daniels SK, Brailey K, Priestly DH, Herrington LR, Weisberg LA. Aspiration in immunodepression. Eur J Neurol. 2013;20:15. patients with acute stroke. Arch Phys Med Rehabil. 1998;79:14-9. 6. Venketasubramanian N, Seshadri R, Chee N. Vocal cord paresis in acute ischemic 3. Shaw GL. Airway obstruction due to bilateral vocal cord paralysis as a stroke. Cerebrovasc Dis. 1999; 9:157-62. complication of stroke. South Med J. 1987; 80:1432-3. 7. Nasrat T, Jouni A, Aresene C, Norris GM. Bilateral Vocal Cord Paralysis with Acute 4. Agur AMR, Dalley AF. Grant’s Atlas of Anatomy. Philadelphia: Lippincott Williams Ischemic Stroke. Ibnosina J Me & Wilkins. 2009.

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76 NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 Netherlands Journal of Critical Care Submitted June 2017; Accepted February 2018

CASE REPORT

Hepatopulmonary syndrome – a rare cause of hypoxaemia

W.A.C. Koekkoek1, C.R. Lamers1, R. Meiland2, M.J. van der Veen3, D.C. Burgers – Bonthuis4 Departments of 1Internal Medicine, 2Gastroenterology and Hepatology, 3Cardiology, 4Intensive Care Medicine, Gelderse Vallei Hospital, Ede, the Netherlands

Correspondence C.R. Lamers - [email protected]

Keywords - hepatopulmonary syndrome; platypnea; orthodeoxia; cirrhosis

Abstract A 61-year-old man presented with a dry cough and dyspnoea. is estimated at 24 months in patients with chronic liver disease On examination, persistent hypoxaemia without clinical signs and HPS compared with 87 months in patients without HPS. of respiratory distress was observed. After the most common Five-year survival is 23% versus 63% in patients without HPS[2,5] causes of hypoxaemia were ruled out, hepatopulmonary Currently, liver transplantation is the only curative therapy syndrome was suspected because of his medical history available. Since HPS is reversible or partially reversible after of liver cirrhosis. Further diagnostic testing including liver transplantation and has a high mortality rate when left serial arterial blood gas analysis and contrast enhanced untreated, patients diagnosed with HPS are granted high transthoracic echocardiography supported the diagnosis. As priority on the transplant waiting list regardless of the MELD liver transplantation is currently the only available curative score. Concurrent with increasing severity of the HPS, the treatment, the patient was referred to a transplantation centre. perioperative risks of liver transplantation increase and Hepatopulmonary syndrome is a rare but severe pulmonary reversibility decreases.[2,3,6] We present a case and briefly review complication of several liver diseases, characterised by arterial the pathogenesis, diagnostic considerations and treatment deoxygenation and intrapulmonary vascular dilatation. When options of HPS based on the currently available evidence. left untreated it has a high mortality rate. Early recognition may increase survival and lower perioperative transplantation Case report risks. Therefore, when encountering a case of unexplained A 61-year-old man was admitted to the surgical ward for total hypoxaemia in a patient with liver disease, the possibility of hip replacement surgery because of femoral head avascular hepatopulmonary syndrome should be considered. necrosis. His medical history revealed liver cirrhosis (Child- Pugh B) with refractory ascites in 2011, which was treated with Introduction the placement of a transjugular intrahepatic portosystemic shunt Hepatopulmonary syndrome (HPS) is a rare but severe (TIPS). Recently, he had also been admitted to the pulmonary pulmonary complication of several liver diseases. It is ward because of dyspnoea and profound hypoxaemia (pO2 6.2 characterised by the triad of liver disease, arterial deoxygenation kPa and SpO2 82% without oxygen suppletion). At that time and intrapulmonary vascular dilatation (IPVD). The prevalence pneumonia and/or an acute exacerbation of COPD seemed most of HPS in patients with liver disease varies from 4-32%.[1] This likely. He was treated with antibiotics and supplemental oxygen depends on the population studied and the diagnostic criteria and quickly recovered. During hospital admission no fever and methods used. Most patients present with dyspnoea, a non- was observed, inflammatory laboratory parameters remained specific finding which may not be directly recognised as HPS.[2,3] low, and sputum and blood cultures showed no bacterial HPS is related to the severity of the underlying liver disease and growth. However, when oxygen suppletion was decreased the most commonly observed in liver disease caused by hepatitis hypoxaemia recurred (SpO2 75-85%). Pulmonary embolism was B, C or the abuse of alcohol. Child-Pugh and MELD scores are ruled out by a CT pulmonary angiogram. Because the patient higher in patients with HPS and these scores are associated had clinically recovered, despite the severe hypoxaemia, he was with increased mortality.[4] In addition, mortality is increased discharged home with planned outpatient follow-up. in patients with HPS compared with patients without HPS Before surgery, the oxygen levels fluctuated between 88-94%. who have a similar severity of liver disease.[3] Median survival During surgery, an oxygen level of 80% was observed without

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Table 1. Arterial blood gas (ABG) analysis indicating orthodeoxia Endothelin-1 binds to these receptors stimulating NO synthase, ABG in outpatient ABG lying down ABG sitting upright leading to an increased production of NO. In addition, increased clinic (without (10 litres O /min) (10 litres O /min) 2 2 phagocytosis of bacterial endotoxin in the lung also promotes the supplemental O2) pH 7.46 7.38 7.42 activation of NO synthase. Activated intravascular macrophages pCO2 (kPa) 4.0 5.3 4.6 also produce haeme oxygenase leading to increased carbon [2,3,8,9] pO2 (kPa) 6.2 8.7 7.4 monoxide which also enhances vasodilatation. HCO3 (mmol/l) 21.3 23.3 22.3 Dilatation leads to increased pulmonary blood flow while SaO2 (%) 82 92 88 ventilation remains unchanged, which causes elevated ventilation-perfusion mismatch and arteriovenous shunts. Due to dilatation, the distance for oxygen molecules to traverse to clinical signs of respiratory distress. The patient was admitted bind haemoglobin is increased. This results in red blood cells to the intensive care unit because of persistent hypoxaemia. exiting the pulmonary capillaries before full oxygenation.[3,5,9,10] CT pulmonary angiogram ruled out emboli; there were no Another contributing factor is the hyperdynamic circulation signs of pleural fluid or pulmonary consolidation. However, present in patients with cirrhosis. This causes a decrease in the radiologist observed large crinkled pulmonary vessels transit time of erythrocytes through the alveolar-capillary unit, and suspected pulmonary hypertension. On additional further compromising oxygen diffusion.[7,9] In addition, the echocardiography low pulmonary artery pressure was found. hypoxaemia worsens as a result of the vasoconstrictive response At that time, the combination of persistent hypoxaemia without of the blood vessels to hypoxaemia, especially in the lower zones clinical signs of respiratory distress, the dilated pulmonary of the lungs where there is less ventilation.[3,10] Finally, patients vessels, the medical history of liver cirrhosis and the fact that may have true anatomic arteriovenous shunts, which allow most common pulmonary causes of hypoxaemia had been ruled blood to completely bypass alveoli, resulting in a mixture of out, led to the suspicion of hepatopulmonary syndrome. pulmonary arterial and venous blood, leading to hypoxaemia.[2,3] Diagnostic testing was performed by serial arterial blood gas There is evidence that not only pulmonary dilatation but also analysis in supine and upright position. Saturation and blood pulmonary angiogenesis causes impaired gas exchange in HPS. oxygen levels were higher in supine position compared with In patients with liver cirrhosis, dissemination of gut bacteria upright position indicating orthodeoxia, which supports the through the body takes place due to disruption of gut mucosal diagnosis of hepatopulmonary syndrome (table 1). Contrast barriers and impaired host defence.[11] Angiogenesis may result enhanced transthoracic echocardiography revealed a right to from accumulation of pulmonary intravascular monocytes due left shunt of microbubbles appearing within 3-6 heart beats. to bacterial translocation, which causes activation of vascular This finding suggests intrapulmonary vascular dilatation and is endothelial growth factor contributing to angiogenesis.[2,3] pathognomonic of hepatopulmonary syndrome. A hepatologist in an academic medical centre was consulted Clinical symptoms and advised screening for liver transplantation. The patient was Platypnoea - an increase in dyspnoea while upright and relief transferred to a liver transplantation centre. Unfortunately, the while supine - and orthodeoxia - hypoxaemia exacerbated in work-up showed incurable renal cell carcinoma, and therefore the upright position - are characteristic for HPS, although not liver transplantation was no longer an option. pathognomonic. Patients can present a variety of other aspecific symptoms. Symptoms concurrent with chronic liver disease Discussion may be observed including anorexia, ascites, hepatomegaly, Pathophysiology splenomegaly, icterus, clubbing, caput medusa, generalised In hepatopulmonary syndrome (HPS), there is dilatation of the oedema and asterixis (flapping tremor). Spider naevi are a pulmonary precapillary and capillary vessels (8-15 µm to 15-160 marker of IPVD and are due to a direct connection between the µm), especially in the lower lobes. Due to this intrapulmonary arterial and venous system.[4,5,8,10] vasodilatation, arterial deoxygenation occurs by three mechanisms: ventilation-perfusion mismatch, limitation of Diagnosis oxygen diffusion and intrapulmonary shunting.[3,7] There are three diagnostic criteria: liver disease, arterial The pathophysiology of the dilatation has not been completely deoxygenation and IPVD. elucidated. Nitric oxide (NO) has been linked to the dilatation because increased NO levels were seen in cirrhotic patients In most patients, the diagnosis of liver disease is already with HPS and NO levels normalised after liver transplantation. established. As diagnostic testing for a variety of liver diseases Animal studies showed an increase of pulmonary endothelin-B is beyond the scope of this report, we will not further address it. receptors due to shear stress caused by cirrhosis and portal Arterial deoxygenation can be diagnosed by arterial blood gas hypertension. Liver injury stimulates release of endothelin-1. analysis. Since orthodeoxia is typically seen in patients with HPS,

78 NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 Netherlands Journal of Critical Care Hepatopulmonary syndrome as a rare cause of hypoxaemia

serial blood gas analysis with the patient lying down then sitting vascular bed due to intrapulmonary vascular dilatation. For upright is preferred. Orthodeoxia is defined as a decrease in SaO2 correct diagnosis the number of heart beats has to be counted. of ≥4 mmHg or ≥5% from the supine to the upright position. It is When microbubbles are in the left atrium within three cardiac a consequence of the increased ventilation-perfusion mismatch cycles, an intracardiac shunt has to be considered. In case of and decreased cardiac output when changing from the supine to an intrapulmonary shunt like IPVD, it takes three to six cardiac the upright position and therefore not exclusively seen in HPS. It cycles for microbubbles to enter the left atrium (video 1).[2,7,13,14] may also occur in patients with other causes of intrapulmonary Other tests include chest radiographs, lung function tests, shunting and/or ventilation-perfusion mismatch or patients with high resolution computed tomography (HR-CT), technetium intracardiac shunting.[7,12] scan and pulmonary angiography. Chest radiographs can

Furthermore, the severity of HPS is graded based on the PaO2 in show nonspecific bibasilar interstitial changes, but are mostly arterial blood gas analysis. This should be drawn with the patient normal. Lung function tests demonstrate a normal spirometry sitting upright at rest on room air. In HPS there is an elevated and lung volumes, but a reduced carbon monoxide diffusion age-corrected alveolar-arterial (A-a) oxygen gradient ≥15 mmHg capacity. However, this is not specific for HPS.[8,13] HR-CT may [5,10,13] (2 kPa) and a PaO2 of <80 mmHg (10.7 kPa) (table 2). show dilated peripheral pulmonary vessels and an increased pulmonary artery to bronchus ratio, two characteristic findings Table 2. Grading system for disease severity of IPVD (figure 1).[13,15] This ratio is defined as the diameter of a Degree of severity PaO 2 pulmonary artery divided by the diameter of its accompanying Mild Partial pressure of oxygen ≥80 mmHg bronchus. It is usually taken as being around 1:1.[16] In Moderate Partial pressure of oxygen ≥60 to <80 mmHg technetium-macroaggregated albumin perfusion lung scanning, Severe Partial pressure of oxygen ≥50 to <60 mmHg aggregated albumin particles are injected intravenously. Very severe Partial pressure of oxygen <50 mmHg Ordinarily, these particles are trapped in the pulmonary <300 mmHg while breathing 100% oxygen microvasculature. In HPS patients, a fraction passes through due to IPVD and gets trapped in capillary beds in organs such as the brain, kidneys, liver and spleen. This allows the calculation The most sensitive and commonly used test to detect IPVD of the shunt fraction, although this scan cannot differentiate is contrast-enhanced transthoracic echocardiography.[9,13] intracardiac from intrapulmonary shunting.[2,8,13] Pulmonary It is performed by injecting agitated saline, a mixture of 9 angiography is an invasive test and not routinely performed. ml physiological saline (NaCl 0.9%) and 1 ml air, creating Based on angiographic patterns, HPS can be classified into two microbubbles. These microbubbles enter the right atrium, then types. Type 1 manifests as an increase in the number of visible the right ventricle and pulmonary branches. Under normal vessels with minimal to extensive vascular dilatation. Type 2 circumstances the microbubbles do not cross the pulmonary demonstrates anatomic arteriovenous communications.[2,13] vascular bed and will not enter the left atrium due to their large size. In case of HPS, microbubbles can cross the pulmonary Treatment Long-term oxygen therapy is the most recommended therapy in patients with severe or very severe HPS to improve features related to intrapulmonary vascular shunts. In the medical therapeutic options investigated only pentoxifylline and methylene blue have shown some possible benefit, although no clear scientific evidence is available and no randomised trials have been performed.[2,7,8,13] In early case reports it was suggested that the use of a transjugular intrahepatic portosystemic shunt (TIPS), to reduce portal hypertension and improve oxygenation, was associated with a better clinical outcome. However, randomised controlled trials are lacking and more recent case reports suggest that improved oxygenation after TIPS causes a hyperdynamic circulation which may worsen HPS.[7] Liver transplantation is currently the only known effective therapy for HPS and should be considered in patients with severe to very [2,7,8,13] severe hypoxaemia (PaO2 <60 mmHg). Due to their high pre- and post-transplantation mortality, patients with HPS are prioritised on the transplant waiting list regardless of the MELD Figure 1. CT pulmonary angiogram of our patient score leading to a pre-transplantation mortality rate of 8.8%.[6-8]

NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 79 Netherlands Journal of Critical Care Hepatopulmonary syndrome as a rare cause of hypoxaemia

Perioperative risks and management which contrast-enhanced transthoracic echocardiography is During liver transplantation, it can be challenging to maintain commonly used to detect dilatation. Liver transplantation is satisfactory oxygen levels, although patients usually respond to currently the only available curative treatment. 100% inspired oxygen.[17,18] Studies suggest monitoring mixed venous oxygen levels for guidance in the need of initiating Disclosures [17,18] venovenous bypass (when SvO2 falls below 65%). Supine All authors declare no conflict of interest. No funding or positioning, and if necessary, Trendelenburg positioning financial support was received. can increase oxygenation. A study comparing the method of anaesthesia (inhalation versus intravenous) showed no differences in oxygenation 30 minutes after induction.[17] References

1. Pascasio JM, Grilo I, López-Pardo FJ, et al. Prevalence and Severity of Postoperative ICU management Hepatopulmonary Syndrome and Its Influence on Survival in Cirrhotic Patients Severe post-transplant hypoxaemia is seen in 6-21% of patients. Evaluated for Liver Transplantation. Am J Transplant. 2014;14:1391-9. 2. Lv Y, Fan D. Hepatopulmonary Syndrome. Dig Dis Sci. 2015;60:1914-23. This is defined as a need for 100% inspired oxygen, with PEEP 3. Grace JA, Angus PW. Hepatopulmonary syndrome: Update on recent advances ≥10 mmHg to maintain oxygen levels >85%. This complication in pathophysiology, investigation, and treatment. J Gastroenterol Hepatol. 2013;28:213-9. [19] has a mortality risk of 45%. Arterial oxygenation is expected to 4. Younis I, Sarwar S, Butt Z, et al. Clinical characteristics, predictors, and survival worsen in the hours immediately post-transplant.[17,18] This is due among patients with hepatopulmonary syndrome. Ann Hepatol. 2015;14:354-60. 5. Rodríguez-Roisin R, Krowka MJ. Hepatopulmonary Syndrome – A Liver-Induced to the abrupt postoperative reversal of pulmonary vasodilatation Lung Vascular Disorder. N Engl J Med. 2008;358:2378-87. leading to pulmonary vasoconstriction increasing the ventilation/ 6. Goldberg DS, Krok K, Batra S, et al. Impact of the Hepatopulmonary Syndrome MELD Exception Policy on Outcomes of Patients After Liver Transplantation. [17,18] perfusion mismatch. Furthermore, narcotics, sedatives, Gastroenterology. 2014;146:1256-65. volume overload and atelectasis may contribute to postoperative 7. Porres-Aguilar M, Altamirano JT, Torre-Delgadillo A, et al. Portopulmonary hypertension and hepatopulmonary syndrome: a clinician-oriented overview. [17,18] hypoxaemia. Nayyar et al. proposed an algorithm for the Eur Respir Rev. 2012;21:223-33. management of severe post-transplant hypoxaemia in HPS based 8. Machicao VI, Fallon MB. Hepatopulmonary Syndrome. Semin Respir Crit Care Med. 2012;33:11-6. on the available literature. The algorithm recommended therapies 9. Raevens S, Geerts A, Van Steenkiste C, et al. Hepatopulmonary syndrome and including Trendelenburg position, inhaled epoprostenol or nitric portopulmonary hypertension: recent knowledge in pathogenesis and overview of clinical assessment. Liver Int. 2015;35:1646-60. oxide, methylene blue, embolisation of abnormal pulmonary 10. Tumgor G. Cirrhosis and hepatopulmonary syndrome. World J Gastroenterol. vessels and extracorporeal life support.[19] 2014;20:2586-94. 11. Eshraghian A, Kamyab AA, Yoon SK. Pharmacological Treatment for Hepatopulmonary Syndrome. Biomed Res Int. 2013; 2013:670139. Prognosis 12. Agrawal A, Palkar A, Talwar A. The multiple dimensions of Platypnea-Orthodeoxia syndrome: A review. Respir Med. 2017;129:31-8. Improvement of arterial deoxygenation and intrapulmonary 13. Grilo-Bensusan I, Pascasio-Acevedo JM. Hepatopulmonary syndrome: What we know and what we would like to know. World J Gastroenterol. 2016;22:5728-41. vascular dilatation occurs almost universally post-transplant. 14. Senior R, Becher H, Monaghan M, et al. Contrast echocardiography: evidence- In >85% of patients liver transplantation results in complete based recommendations by European Association of Echocardiography. Eur J Echocardiogr. 2009;10:194-212. resolution of HPS or significant improvement in gas exchange 15. Köksal D, Kaçar S, Köksal AS, et al. Evaluation of Intrapulmonary Vascular within the first 6-12 months post-transplant.[7] The 5-year Dilatations With High-Resolution Computed Thorax Tomography in Patients With Hepatopulmonary Syndrome. J Clin Gastroenterol. 2006;40:77-83. survival rate of patients with HPS after liver transplantation is 16. Woodring JH. Pulmonary artery-Bronchus Ratios in Patients with Normal 76%, which is comparable with cirrhotic patients without HPS Lungs, Pulmonary Vascular Plethora, and Congestive Heart Failure. Radiology. [6,8] 1991;179:115-22. undergoing liver transplantation. 17. Krowka MJ, Fallon MB, Kawut SM, et al. International Liver Transplant Society Practice Guidelines: Diagnosis and Management of Hepatopulmonary Syndrome Conclusion and Portopulmonary Hyeprtension. Transplantation. 2016;100:1440-52. 18. Iqbal S, Smith KA, Khungar V. Hepatopulmonary Syndrome and Portopulmonary Hepatopulmonary syndrome is a rare but severe pulmonary Hypertension. Implications for Liver Transplantation. Clin Chest Med. 2017;38:785-95. 19. Nayyar D, Man HSJ, Granton J, et al. Proposed Management Algorithm for Severe complication of several liver diseases in which platypnoea Hypoxemia After Liver Transplantation in the Hepatopulmonary Syndrome. Am J and orthodeoxia are seen. Diagnostic criteria include arterial Transplant. 2015;15:903-13. deoxygenation and intrapulmonary vascular dilatation for Video file 1: Contrast-enhanced transthoracic echocardiography (apical four chamber view): microbubbles entering the left atrium within three to six cardiac cycles after entering the right atrium.

https://www.njcc.nl/njcc-d-17-00050-lamers

80 NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 Netherlands Journal of Critical Care Submitted December 2017; Accepted January 2017

RESEARCH NEWS

Lung recruitment and titrated PEEP in moderate to severe ARDS

J. Pillay Department of Intensive Care, Academic Medical Center Amsterdam, the Netherlands

Correspondence J. Pillay - [email protected]

Keywords - ARDS, recruitment, PEEP

Article reasons for exclusion were P/F ratio >200 after standard Effect of lung recruitment and titrated PEEP vs. low PEEP ventilation (296 patients), increasing dose of vasoconstrictor on mortality in patients with ARDS. Published in JAMA, in or mean arterial pressure <65 (273 patients), pneumothorax October 2017.[1] or pneumomediastinum (139 patients) and contraindications to hypercapnia (129 patients). The remaining patients were Why was this research done? randomised to receive lung recruitment and PEEP titrated ARDS causes collapse, flooding and consolidations in large according to the best lung compliance (501 patients) or low parts of the lung. This increases the risk of ventilator-induced PEEP without recruitment (512 patients). lung injury due to over-distention of aerated lung and cyclic In the RM and titrated PEEP group patients received opening and closing of collapsed alveoli (atelectrauma). neuromuscular blocking agents and fluid loading in preparation To reduce ventilator-induced lung injury, the open lung for the RM. RM consisted of incremental PEEP up to 45 cm concept has been advocated and is accepted practice in many H2O followed by decremental PEEP titration to best lung

ICUs. Recruiting collapsed lung regions using recruitment compliance. PEEP was set at this level + 2 cm H2O. In the low- manoeuvers (RM) and applying PEEP to keep these regions PEEP group PEEP was set according to the ARDSnet table. In open reduces atelectrauma and more evenly distributes the both groups, patients were ventilated with 6 ml/kg (or less) tidal tidal volume, thus limiting over-distention of the aerated lung. volumes and plateau pressures were kept under 30 cm H2O. The level of PEEP needed and how to determine this for the The primary endpoint was 28-day all-cause mortality. Secondary individual patient is, however, unknown. endpoints were length of ICU and hospital stay, ventilator-free Three large RCTs applying high PEEP and RM in patients with days, pneumothorax requiring drainage or barotrauma within 7 ARDS (P/F ratio <300) did not show an effect on mortality.[2-4] days, and ICU, in hospital and 6-month mortality. However, a meta-analysis of these trials suggested a reduction in mortality in patients with a P/F ratio <200.[5] Main findings This RCT was conducted to study the effect of RM and titrated Compared with the control group, RM and titrated PEEP PEEP on mortality in moderate to severe ARDS (P/F ratio < 200). increased 28-day all-cause mortality (55.3% vs 49.3%; hazard ratio [HR] 1.20; 95% CI 1.01 to 1.42; p=0.041). In addition, What was the research question? 6-month mortality was increased (65.3% vs 59.9%; HR 1.18; 95% Does a strategy of lung recruitment and titrated PEEP vs. no CI 1.01 to 1.38; p=0.04) and ventilator-free days were decreased recruitment and low PEEP reduce 28-day mortality in patients (5.3 vs 6.4; 95% CI -2.1 to -0.3; p=0.03). The RM and titrated with moderate to severe ARDS? PEEP group showed an increased risk of pneumothorax (3.2% vs 1.2%; 95% CI 0.0% to 4.0%; p=0.03) and barotrauma (5.6% vs How was this investigated? 1.6%; 95% CI 1.1% to 6.5%; p=0.01).

The authors performed a multicentre randomised controlled PEEP in the intervention group was 3-4 cm H2O higher over trial in 120 ICUs from 9 countries. Patients were included over the first 7 days. The mean P/F ratios were higher in the RM and a 6-year period. titrated PEEP group; however, the decrease in driving pressure

A total of 1013 patients with moderate to severe ARDS were in this group was less than 2cm H2O compared with the control randomised after exclusion of 1064 patients. The main group.

NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 81 Netherlands Journal of Critical Care

Discussion, conclusion and consequences for daily practice In conclusion, this study emphasises the risk of RM and This large multicentre RCT studied two interventions (RM and questions the routine use of titrated PEEP in patients with high PEEP) to ‘open up the lung and keep it open’ and compared moderate to severe ARDS. this with a strategy of low PEEP, set according to the ARDSnet table. It shows that RM and titrated PEEP increases mortality Disclosures in patients with moderate to severe ARDS. It has previously The author declares no conflict of interest. No funding or been shown that high PEEP does not influence mortality in a financial support was received. study group consisting of mild, moderate and severe ARDS;[2-4] however, no or milder recruitment manoeuvers were used in References those studies. In this study, there was a relatively small difference 1. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress in the PEEP levels between the experimental and control group Syndrome Trial (ART) Investigators, Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients (3-4 cm H2O); in addition, the driving pressure was only 2 cm With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. H O lower in the experimental group. This suggests only minimal 2017;318:1335-45. 2 2. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end- recruitment after the RM. It is conceivable that individual expiratory pressures in patients with the acute respiratory distress syndrome. N patients with recruitable lungs might have benefited from an Engl J Med. 2004;351:327-36. 3. Mercat A, Richard JC, Vielle B, et al. Positive end-expiratory pressure setting RM; however, this analysis was not performed. In addition, a in adults with acute lung injury and acute respiratory distress syndrome: a major variable between the two groups was the fluid loading in randomized controlled trial. JAMA. 2008;299:646-55. 4. Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, preparation for an RM. Excessive administration of fluids could recruitment maneuvers, and high positive end-expiratory pressure for acute lung have increased detrimental outcome in the experimental group; injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA. 2008;299:637-45. however, the exact amount of fluids or fluid balances was not 5. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure reported. in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010;303:865-73.

PRESCRIBING INFORMATION dexdor® 100 micrograms per ml concentrate for solution for infusion (dexmedetomidine) Prescribing Information. Indication: Sedation of adult ICU patients requiring sedation level not deeper than arousal in response to verbal stimulation (RASS 0 to -3). Dosage and administration: Hospital use only, by healthcare professionals skilled in management of patients requiring intensive When care is critical, care. Administer only as diluted intravenous infusion using controlled infusion device. Dexmedetomidine is very potent and the infusion rate is given per hour. Switch patients already intubated and sedated to dexmedetomidine with initial balance is everything infusion rate of 0.7 micrograms/kg/h and adjust stepwise within range 0.2 to 1.4 micrograms/kg/h to achieve desired sedation level. Consider lower starting infusion rate for frail patients. After dose adjustment, new steady state sedation level may not be reached for up to one hour. Do not exceed maximum dose of 1.4 micrograms/kg/h. Switch patients failing to achieve an adequate level of sedation with maximum dose to an alternative sedative agent. Loading dose not recommended. Administer propofol or midazolam if needed until clinical effects of dexdor® established. No experience in use of dexdor® for more than 14 days. Use for longer than this period should be regularly reassessed. Elderly: No dosage adjustment required. Renal impairment: No dosage adjustment required. Hepatic impairment: Caution advised; consider reduced dose. Children aged 0-18 years: Safety and efficacy not established. Contraindica- tions: Hypersensitivity. Advanced heart block (grade 2 or 3) unless paced. Uncontrolled hypotension. Acute cerebrovascular conditions. Warnings and precautions: Intended for use in intensive care setting, use in other environ- ments not recommended. Continuous cardiac monitoring required. Monitor respiration in non-intubated patients due to the risk of respiratory depression and in some cases apnoe. Do not use as induction agent for intubation or to provide sedation during muscle relaxant use. dexdor® reduces heart rate and blood pressure but at higher concentrations causes peripheral vasoconstriction and hypertension. Not suitable in patients who will not tolerate lack of deep sedation and easy rousability. Users should be ready to use alternative sedative for acute control of agitation or during procedures, especially during the first few hours of treatment. Caution with: pre-existing bradycardia; high physical fitness and slow resting heart rate; pre-existing hypotension, hypovo- laemia, chronic hypotension or reduced functional reserve; severe ventricular dysfunction; the elderly; impaired peripheral autonomic activity (e.g. due to spi- nal cord injury); ischaemic heart disease or severe cerebrovascular disease; severe hepatic impairment; severe neurological disorders such as head injury and after neurosurgery. Reduce dose or discontinue if signs of myocardial or cerebral ischaemia. Additive effects may occur with other substances with sedative or cardiovascular actions. Some patients receiving dexdor® have been observed to be arousable and alert when stimulated; this alone should not be considered as evidence of lack of efficacy. Do not use as sole treatment in status epilepticus. Consider possibility of withdrawal reaction if patient develops agitation and hypertension shortly after stopping dexmedetomidine. Not recommended in malignant hyperthermia-sensitive individuals. Discontinue treatment in event of sustained unexplained fever. Undesirable effects: Very common (≥1/10): Bradycardia, hypotension, hypertension. Common (1≥100 to <1/10): Hyperglycaemia, hypoglycaemia, agitation, myocardial ischaemia or infarction, tachycardia, respiratory depression, nausea, vomiting, dry mouth, withdrawal syndrome, hyperthermia. Uncommon (1≥1,000 to <1/100): Metabolic acidosis, hypoalbuminaemia, hallucination, atrioventricular block first degree, See more of the person, treat more of the patient cardiac output decreased,dyspnoea, apnoea, abdominal distension, drug inef- fective, thirst. See SPC for further details. By striking just the right balance in sedation, dexdor® optimises pain, agitation and delirium (PAD) management1– 4 in the ICU to Market authorization numbers EU/1/11/718/001-002, EU/1/11/718/004, EU1/11/718/006-007. Date of first autorisation: 16 september 2011. achieve a calm and cooperative patient. With reduced times Date of renewal of the authorization: 26th May 2016 to extubation*1,3 and shorter overall stays in the ICU†5, dexdor® Orion Pharma BVBA • Battelsesteenweg 455D • 2800 Mechelen can help play a critical role in restoring your patient to the Tel: +32 (0) 15 64 10 20 • Fax: +32 (0) 15 64 10 21 • person that they really are.

For further information visit www.dexdor.eu

* vs propofol and vs midazolam † vs propofol or midazolam in pooled analysis

82 NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 Netherlands Journal of Critical Care Submitted October 2017; Accepted January 2018

CORRESPONDENCE

Pro/con debate Conservative oxygenation in the intensive care unit: Pro

H.J.F. Helmerhorst Departments of Intensive Care Medicine and Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands

Correspondence H.J.F. Helmerhorst - [email protected]

Keywords - oxygen therapy, conservative oxygenation, hyperoxia, mechanical ventilation, intensive care unit, pro-con

Owing to its indispensable nature, oxygen may be the most oxygen of 75-100 mmHg (10-13.3 kPa) and corresponding appealing element in life, but it is also a vital element in medical mitochondrial oxygen concentrations of approximately 11 practice and among the most universally used agents for the mmHg (1.5 kPa). One can argue that oxygen delivery and treatment of critically ill patients. In order to ensure sufficient tissue oxygen tension not only depend on the arterial oxygen oxygenation, oxygen therapy during mechanical ventilation, tension but also on perfusion and oxygen consumption. These anaesthesia and resuscitation usually exceeds physiological two factors are frequently impacted by critical illness and may levels. It is highly effective in increasing the oxygen content of vary in different tissues, and at different temperatures and pH. arterial blood when tissues are at risk of a critical deficiency in However, higher oxygen concentrations have been shown to oxygen concentrations. increase the peripheral vascular resistance and decrease cardiac However, physiological concepts, preclinical data and recent output.[10,11] As a result oxygen delivery in the organs at risk clinical studies suggest that excessive oxygenation can have may actually be impaired through peripheral vasoconstriction significant deleterious properties in various sequelae of disease and bradycardia. Hyperoxia-induced haemodynamic changes and may lead to a paradoxical decrease in oxygen delivery to impose a further risk during cardiovascular instability. Likewise, prone regional areas.[1-3] Because an excess of oxygen is difficult increased mortality and morbidity have been observed with to monitor on a continuous basis and oxygen is generally hyperoxia during events such as ischaemic heart disease,[12,13] administered in a liberal manner, arterial hyperoxia is frequently cardiac arrest,[14,15] stroke,[16,17] traumatic brain injury[18-21] and encountered in the intensive care unit.[4-6] Hyperoxia can be mechanical ventilation.[22,23] The relationship between arterial defined as a state in which supraphysiological levels of oxygen hyperoxia and hospital mortality is quite consistent over several are inspired and/or reach the arterial circulation. A formal subgroups, but associations with delayed cerebral ischaemia, definition for arterial hyperoxia does not exist, but a partial poor cerebral performance and disability have also been shown pressure of arterial oxygen (PaO2) higher than 120 mmHg (>16 in patients after cardiac arrest, traumatic brain injury and kPa) has previously been characterised as mild hyperoxia and stroke.[23,24] Also, a decline in ventilation-free days (28 days after

PaO2 >200 mmHg (26.7 kPa) as severe hyperoxia. admission) have been observed in patients where the average [24] Several studies indicate that targeting conservative oxygenation PaO2 over the ICU admission time was larger than 200 mmHg. or at least normoxia after initiation of mechanical ventilation Another pathway through which conservative oxygenation is safe, may prevent complications and improve patient-centred may be favourable in comparison with hyperoxygenation outcomes.[7-9] Conservative oxygen therapy may contribute to is by establishing a healthy balance between oxidants and acclimatisation and cellular adaptation to the lower ranges of antioxidants. Oxygen free radicals, which are commonly referred normoxia, which may result in improved efficiency of adenosine to as reactive oxygen species (ROS), are versatile molecules with triphosphate production and protection of mitochondria. From an important role in cell signalling and homeostasis. ROS are a physiological point of view this makes perfect sense as the formed during aerobic metabolism but physiological levels may human body has evolutionarily been adapted to successfully be exceeded during environmental stress or when supplemental maintain aerobic metabolism with a fraction of inspired oxygen oxygen is administered. Critical illness may be viewed as an

(FiO2) of 21% in ambient air at sea level. It provides the ideal important environmental stressor and a typical setting for environment for the eukaryotic cell that is perfectly capable of inadequate levels of ROS. When antioxidant systems are efficient oxygen consumption at partial pressures of arterial insufficient, supplemental oxygen can cause accumulation of

NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 83 Netherlands Journal of Critical Care Conservative oxygenation in the ICU: Pro

oxygen radicals and may initiate or perpetuate oxygen toxicity. conservative approach by targeting relative normoxia at As a result of ROS and damage associated molecular pattern physiological levels and avoiding exposure to sub-physiological (DAMP) molecules, DNA and cell damage may manifest as as well as supraphysiological oxygenation should be considered apoptosis and necrosis leading to tissue injury and local organ- the most rational choice in most cases. In selected patients, specific complications. DNA damage has been suggested to targeting the lower ranges of normoxia (55-80 mmHg) may also underlie the worse outcomes of patients exposed to high FiO2 be safely pursued, but this remains to be confirmed in future levels during oncological surgery.[25,26] Pathways of cell damage clinical trials. and oxidative stress contribute to a pro-inflammatory state in which tissue injury is exaggerated and the innate immune Disclosures system may be impaired.[27] The author declares no conflict of interest. No funding or Interestingly, it has long been suggested that hyperoxia may financial support was received. have antibacterial properties and can reduce surgical site infections (SSI) or infectious complications, but in recent meta- References [28,29] analyses this effect appeared to be marginal or even absent. 1. Helmerhorst HJ, Schultz MJ, van der Voort PH, de Jonge E, van Westerloo DJ. A lively debate has only recently been launched in reaction to Bench-to-bedside review: the effects of hyperoxia during critical illness. Crit Care. 2015;19:284. a recommendation by the World Health Organisation (WHO) 2. Altemeier WA, Sinclair SE. Hyperoxia in the intensive care unit: why more is not stating that ‘adult patients undergoing general anaesthesia with always better. Curr Opin Crit Care. 2007;13:73-8. 3. Sjoberg F, Singer M. The medical use of oxygen: a time for critical reappraisal. J endotracheal intubation for surgical procedures should receive Intern Med. 2013;274:505-28. 80% fraction of inspired oxygen intraoperatively and, if feasible, 4. de Graaff AE, Dongelmans DA, Binnekade JM, de Jonge E. Clinicians' response to hyperoxia in ventilated patients in a Dutch ICU depends on the level of FiO2. in the immediate postoperative period for 2-6 hrs’. Intensive Care Med. 2011;37:46-51. The rationale for such measures is to improve oxidative 5. Panwar R, Capellier G, Schmutz N, et al. Current oxygenation practice in ventilated patients-an observational cohort study. Anaesth Intensive Care. 2013;41:505-14. killing of bacteria by neutrophils. However, not only was there 6. Suzuki S, Eastwood GM, Peck L, Glassford NJ, Bellomo R. Current oxygen insufficient evidence from methodologically limited studies management in mechanically ventilated patients: a prospective observational cohort study. J Crit Care. 2013;28:647-54. with heterogeneous outcomes, but other effects of hyperoxic 7. Girardis M, Busani S, Damiani E, et al. Effect of Conservative vs Conventional ventilation were completely ignored in this international Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016;316:1583-9. recommendation. The concept of a beneficial effect of hyperoxia 8. Helmerhorst HJ, Schultz MJ, van der Voort PH, et al. Effectiveness and Clinical on infections emerged when an experimental study showed Outcomes of a Two-Step Implementation of Conservative Oxygenation Targets in Critically Ill Patients: A Before and After Trial. Crit Care Med. 2016;44:554-63. that SSI may occur less frequently when subcutaneous tissue 9. Panwar R, Hardie M, Bellomo R, et al. Conservative Versus Liberal Oxygenation oxygen tensions stay above 60-80 mmHg, which happens when Targets for Mechanically Ventilated Patients - a Pilot Multicenter Randomized Controlled Trial. Am J Respir Crit Care Med. 2016;193:43-51. [30] PaO2 levels are higher than 300 mmHg. It is exactly at those 10. Bak Z, Sjoberg F, Rousseau A, Steinvall I, Janerot-Sjoberg B. Human cardiovascular levels where the risk of in-hospital death has been shown to rise dose-response to supplemental oxygen. Acta Physiologica. 2007;191:15-24. 11. Helmerhorst HJF, de Wilde RBP, Lee DH, et al. Hemodynamic effects of short-term sharply in critically ill patients,[24] especially when the exposure hyperoxia after coronary artery bypass grafting. Ann Intensive Care. 2017;7:20. 12. Stub D, Smith K, Bernard S, et al. Air Versus Oxygen in ST-Segment-Elevation to such supraphysiological levels is prolonged. Also, a more Myocardial Infarction. Circulation. 2015;131:2143-50. complete Cochrane review of the literature in 2015 concluded 13. Farquhar H, Weatherall M, Wijesinghe M, et al. Systematic review of studies of the effect of hyperoxia on coronary blood flow. Am Heart J. 2009;158:371-7. that evidence does not support the routine use of FiO2 higher 14. Helmerhorst HJ, Roos-Blom MJ, van Westerloo DJ, Abu-Hanna A, de Keizer than 60% during anaesthesia and surgery, as the risk of adverse NF, de Jonge E. Associations of arterial carbon dioxide and arterial oxygen concentrations with hospital mortality after resuscitation from cardiac arrest. Crit events, including mortality, may be increased by a fraction of Care. 2015;19:348. inspired oxygen of 60% or higher.[31] 15. Kilgannon JH, Jones AE, Shapiro NI, et al. Association Between Arterial Hyperoxia Following Resuscitation From Cardiac Arrest and In-Hospital Mortality. JAMA. Furthermore, neurological symptoms following hyperoxic 2010;303:2165-71. ventilation can be transient or severe but are usually less 16. Rincon F, Kang J, Maltenfort M, et al. Association between hyperoxia and mortality after stroke: a multicenter cohort study. Crit Care Med. 2014;42:387-96. pertinent and difficult to diagnose in sedated critically ill 17. Jeon SB, Choi HA, Badjatia N, et al. Hyperoxia may be related to delayed cerebral patients. Pulmonary complications are more frequently ischemia and poor outcome after subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014;85:1301-7 encountered as absorption atelectasis, inflammation and 18. Asher SR, Curry P, Sharma D, et al. Survival advantage and PaO2 threshold in pulmonary oedema can have major influence on oxygenation severe traumatic brain injury. J Neurosurg Anesthesiol. 2013;25:168-73. 19. Brenner M, Stein D, Hu P, Kufera J, Wooford M, Scalea T. Association between and ventilation. early hyperoxia and worse outcomes after traumatic brain injury. Arch Surg. 2012;147:1042-6. 20. Raj R, Bendel S, Reinikainen M, et al. Hyperoxemia and long-term outcome after In conclusion, the side effects of supraphysiological oxygenation traumatic brain injury. Crit Care. 2013;17:R177. can be roughly subdivided in cell damage, inflammation, 21. Rincon F, Kang J, Vibbert M, Urtecho J, Athar MK, Jallo J. Significance of arterial hyperoxia and relationship with case fatality in traumatic brain injury: a pulmonary complications, neurological symptoms and multicentre cohort study. J Neurol Neurosurg Psychiatry. 2014;85:799-805. vascular effects. These major features are responsible for 22. de Jonge E, Peelen L, Keijzers PJ, et al. Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive the large majority of the unfavourable effects associated with care unit patients. Crit Care. 2008;12:R156. the (prolonged) exposure to hyperoxia. Therefore, a more

84 NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 Netherlands Journal of Critical Care Conservative oxygenation in the ICU: Pro

23. Helmerhorst HJ, Roos-Blom MJ, van Westerloo DJ, de Jonge E. Association 28. Togioka B, Galvagno S, Sumida S, Murphy J, Ouanes JP, Wu C. The role of Between Arterial Hyperoxia and Outcome in Subsets of Critical Illness: A perioperative high inspired oxygen therapy in reducing surgical site infection: a Systematic Review, Meta-Analysis, and Meta-Regression of Cohort Studies. Crit meta-analysis. Anesth Analg. 2012;114:334-42. Care Med. 2015;43:1508-19. 29. Yang W, Liu Y, Zhang Y, Zhao QH, He SF. Effect of intra-operative high inspired 24. Helmerhorst HJ, Arts DL, Schultz MJ, et al. Metrics of Arterial Hyperoxia and oxygen fraction on surgical site infection: a meta-analysis of randomized Associated Outcomes in Critical Care. Crit Care Med. 2017;45:187-95. controlled trials. J Hosp Infect. 2016;93:329-38. 25. Meyhoff CS, Jorgensen LN, Wetterslev J, Christensen KB, Rasmussen LS, Group 30. Gottrup F, Firmin R, Rabkin J, Halliday BJ, Hunt TK. Directly measured tissue PT. Increased long-term mortality after a high perioperative inspiratory oxygen oxygen tension and arterial oxygen tension assess tissue perfusion. Crit Care fraction during abdominal surgery: follow-up of a randomized clinical trial. Med. 1987;15:1030-6. Anesth Analg. 2012;115:849-54. 31. Wetterslev J, Meyhoff CS, Jorgensen LN, Gluud C, Lindschou J, Rasmussen LS. 26. Meyhoff CS, Jorgensen LN, Wetterslev J, Siersma VD, Rasmussen LS, Group PT. Risk The effects of high perioperative inspiratory oxygen fraction for adult surgical of new or recurrent cancer after a high perioperative inspiratory oxygen fraction patients. Cochrane Database Syst Rev. 2015(6):CD008884. during abdominal surgery. Br J Anaesth. 2014;113 Suppl 1:i74-i81. 27. Helmerhorst HJF, Schouten LRA, Wagenaar GTM, et al. Hyperoxia provokes a time- and dose-dependent inflammatory response in mechanically ventilated mice, irrespective of tidal volumes. Intensive Care Med Exp. 2017;5:27.

NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 85 Netherlands Journal of Critical Care Submitted November 2017; Accepted January 2018

CORRESPONDENCE

Pro/con debate Conservative oxygenation in the intensive care unit: Con

A.M.E. Spoelstra – de Man Department of Intensive Care, VU University Medical Center, the Netherlands

Correspondence A.M.E. Spoelstra - [email protected]

Keywords - hyperoxia, oxidative stress, reactive oxygen species

In the last decade, the attitude towards oxygen therapy for retrospective design. Thereby, hyperoxia could just have been ICU patients has changed. Whereas in earlier times we used a marker for severity of illness.[7] Mostly, only the blood gas to administer oxygen superfluously to prevent hypoxaemia, measurements of the first 24 hours were taken into account[8-10] recently we have become increasingly aware of the potential and classification of hyperoxia based on a single blood gas harmful effects of hyperoxaemia.[1] Many papers urge us to aim analysis (highest A-a gradient,[9] lowest P/F ratio11). Therefore, for tight oxygen control. However, we have to be careful not to the effect of cumulative oxygen exposure during the entire ICU jump to conclusions, as was the case for tight glucose control. or hospital stay in these studies was unknown. Numerous adverse effects of hyperoxia have been reported, In the observational studies that differentiated between mild, pathophysiologically based on an increase in oxidative stress moderate and severe hyperoxia, severe hyperoxia was rather and inflammation. Among the most frequently reported are consistently associated with worse outcome,[10,12,13] whereas pulmonary side effects, such as tracheobronchitis, resorption mild to moderate hyperoxia improved outcome in a number of atelectasis and pulmonary oedema. These effects are studies.[10,12] For example, after cardiac arrest, severe hyperoxia directly proportional to PaO2 (especially with FiO2 ≥0.6) and (defined as PaO2 >300 mmHg) was associated with increased [2] exposure time. Furthermore, hyperoxia can induce systemic mortality, whereas moderate hyperoxia (PaO2 100-299 vasoconstriction, in particular in the coronary and cerebral mmHg) was associated with improved organ function.10 Two vessels, leading to a decrease in cardiac output and organ retrospective studies of patients with traumatic brain injury [3] perfusion and an increase of ischaemia/reperfusion injury. suggested that a PaO2 of 110-487 mmHg12 and 250-486 mmHg, However, besides negative effects, also positive effects can respectively, was associated with the best outcome.[13] be ascribed to hyperoxia. The reported vasoconstriction may Furthermore, the nadir of mortality in several observational be beneficial. Preclinical studies indicate that hyperoxia- studies appeared to be in the mild hyperoxic, rather than induced vasoconstriction may stabilise macrocirculatory and the physiological or subnormal range. In one of the most microcirculatory haemodynamics with improved kidney and important landmark trials with regard to hyperoxia in ICU brain redox state,[4] although these findings were not confirmed patients, the nadir of the U-shaped curve of mortality was at by clinical studies.[5] Hyperoxia can be protective in haemorrhagic 110-150 mmHg,[11] which was supported by the results of two shock, preventing myocardial ischaemia and redistributing large observational cohort studies of the same group showing blood flow in preference of the renal or hepatosplanchnic system the lowest mortality at a mean PaO2 of ~150 mmHg over the [3] [14] with improvement of organ function. In addition, hyperoxia total ICU length of stay in ICU patients and a PaO2 of 180- may enhance bactericidal effects of neutrophils by enhanced 200 mmHg (estimated in the blood gas with the worst P/F ratio reactive oxygen species (ROS) formation and inhibit bacterial in the first 24 hours) in cardiac arrest.[15] Thereby, these results replication, thereby reducing the risk of surgical site infection, suggest that mild to moderate hyperoxia might be equal to or in particular following colorectal surgery.[6] superior to normoxia in terms of outcome. Moreover, subgroup analysis in a recent review of observational At present, good quality clinical data about the effect of cohort studies showed a statistically significant adverse clinical hyperoxia remain limited. Many studies and reviews suggesting outcome in patients with hyperoxia compared to nomoxia that hyperoxia leads to worse outcome and increased mortality for cardiac arrest and ischaemic stroke, but not for traumatic are based on observational data, frequently obtained in a brain injury, intracranial haemorrhage or after cardiac surgery

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(the numbers of patients with haemorrhagic shock, sepsis or be in the normoxic, but in the mild supraphysiological range. The multiple trauma were too low or not quantified).7 This suggests few RCTs at present find equivocal results. Future trials should that the optimal PaO2 range may differ depending on the not investigate the effect of a fixed oxygen suppletion, but should underlying pathophysiological problem of the patient. compare predefined SpO2 or PaO2 values. Also, estimating long-

term effects of subnormal PaO2 levels on cognitive function is

The results of these observational studies urged the need for necessary to assess optimal PaO2 levels for different subgroups. good quality randomised controlled trials (RCTs) in carefully selected patient groups to estimate optimal oxygenation targets. Disclosures In recent years, the results of the first RCTs investigating The author declares no conflict of interest. No funding or different oxygenation strategies have become available, yielding financial support was received. equivocal results. Some RCTs found a worse outcome with hyperoxia, whereas other trials did not show any difference References between normoxia and hyperoxia. With regard to myocardial 1. Vincent JL, Taccone FS, He X. Harmful Effects of Hyperoxia in Postcardiac Arrest, infarction, the AVOID study (investigating non-hypoxaemic Sepsis, Traumatic Brain Injury, or Stroke: The Importance of Individualized Oxygen Therapy in Critically Ill Patients. Can Respir J. 2017: 2834956. patients comparing 8 l O2/min to air) showed increased 2. Kallet RH, Matthay MA. Hyperoxic acute lung injury. Respir Care. 2013;58:123-41. myocardial injury,[16] but a recent Swedish trial (comparing 3. Hafner S, Beloncle F, Koch A, Radermacher P, Asfar P. Hyperoxia in intensive care, emergency, and peri-operative medicine: Dr. Jekyll or Mr. Hyde? A 2015 update. 6 l O2/min to air) did not find a difference in mortality or Ann Intensive Care. 2015; 5:42. high-sensitive troponin T levels.[17] In patients with stroke, 4. Asfar P, Schortgen F, Huber-Lang M, Radermacher P. Hyperoxia in Septic Shock: Crafty Therapeutic Weapon or Double-Edged Sword? Crit Care Med. an RCT studying high flow oxygen at 30-45 l/min for 8 hrs 2017;45:1796-8. was terminated prematurely due to increased mortality in 5. Asfar P, Schortgen F, Boisrame-Helms J, et al. Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, the hyperoxia group, although deaths were not attributed to randomised, clinical trial. Lancet Respir Med. 2017;5:180-90. treatment (NCT00414726). However, in a very large study of 6. Yang W, Liu Y, Zhang Y, Zhao QH, He SF. Effect of intra-operative high inspired oxygen fraction on surgical site infection: a meta-analysis of randomized 8000 non-hypoxic patients with stroke, low-dose oxygen (2 l O2/ controlled trials. J Hosp Infect. 2016;93:329-38. min) did result in a different outcome compared with ambient 7. Helmerhorst HJ, Roos-Blom MJ, van Westerloo DJ, de Jonge E. Association Between Arterial Hyperoxia and Outcome in Subsets of Critical Illness: A [18] air In these four studies, oxygen was applied in a fixed dose Systematic Review, Meta-Analysis, and Meta-Regression of Cohort Studies. Crit without an upper limit in PaO or SpO , so the achieved levels of Care Med. 2015;43:1508-19. 2 2 8. Bellomo R, Bailey M, Eastwood GM, et al. Arterial hyperoxia and in-hospital PaO2 may have varied considerably. Two RCTs in ICU patients mortality after resuscitation from cardiac arrest. Crit Care. 2011;15:R90. compared conservative vs. conventional oxygen therapy and 9. Eastwood G, Bellomo R, Bailey M, et al. Arterial oxygen tension and mortality in mechanically ventilated patients. Intensive Care Med. 2012;38:91-8. titrated the FiO2 based on the SpO2 and PaO2. In the largest 10. Elmer J, Scutella M, Pullalarevu R, et al. The association between hyperoxia and RCT in ICU patients until present (comparing SpO 94-98% vs. patient outcomes after cardiac arrest: analysis of a high-resolution database. 2 Intensive Care Med. 2015;41:49-57. SpO2 >97%), there was a substantial decrease of mortality in the 11. de JE, Peelen L, Keijzers PJ, et al. Association between administered oxygen, [19] arterial partial oxygen pressure and mortality in mechanically ventilated intensive conservative group (11 vs. 20%). However, control of blood care unit patients. Crit Care. 2008;12: R156. gas analysis was scarce, the SpO2 was not reported and the study 12. Davis DP, Meade W, Sise MJ, et al. Both hypoxemia and extreme hyperoxemia may be detrimental in patients with severe traumatic brain injury. J Neurotrauma. was terminated prematurely. Another RCT comparing target 2009;26:2217-23.

SpO2 of 88-92% vs. >96% did not observe a significant difference 13. Asher SR, Curry P, Sharma D, et al. Survival advantage and PaO2 threshold in severe traumatic brain injury. J Neurosurg Anesthesiol. 2013;25:168-73. in mortality; however, this was a small pilot not powered for 14. Helmerhorst HJ, Arts DL, Schultz MJ, et al. Metrics of Arterial Hyperoxia and mortality.[20] The potential downside of tight oxygen control Associated Outcomes in Critical Care. Crit Care Med. 2017;45:187-95. 15. Helmerhorst HJ, Roos-Blom MJ, van Westerloo DJ, Abu-Hanna A, de Keizer NF, de is the increase in subnormal PaO2 levels. Subnormal levels Jonge E. Associations of arterial carbon dioxide and arterial oxygen concentrations such as accepted for ARDS patients (down to 55 mmHg) may with hospital mortality after resuscitation from cardiac arrest. Crit Care. 2015; 19:348. [21] 16. Stub D, Smith K, Bernard S, et al. A randomized controlled trial of oxygen therapy lead to long-term cognitive dysfunction. Since pulmonary in acute ST-segment elevation myocardial infarction: The Air Versus Oxygen in Myocardial Infarction (AVOID) Study". Report of the American Heart Association effects mostly appear at higher FiO2 levels (FiO2 >60%, almost [2,22] (AHA) Scientific Sessions; 2014. no difference in cytokine levels at FiO2 of 30-50% ), it is 17. Hofmann R, James SK, Jernberg T, et al. Oxygen Therapy in Suspected Acute commonly unnecessary in patients without ARDS or other Myocardial Infarction. N Engl J Med. 2017;377: 1240-9. 18. Roffe C, Nevatte T, Sim J, et al. Effect of Routine Low-Dose Oxygen severe pulmonary problems to allow the PaO2 level to decrease Supplementation on Death and Disability in Adults With Acute Stroke: The Stroke Oxygen Study Randomized Clinical Trial. JAMA. 2017;318:1125-35. to this extent to avoid high FiO2 levels. Long-term cognitive 19. Girardis M, Busani S, Damiani E, et al. Effect of Conservative vs. Conventional effects were not estimated in these two RCTs. Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial. JAMA. 2016;316:1583-9. 20. Panwar R, Capellier G, Schmutz N, et al. Current oxygenation practice in ventilated In conclusion, although severe hyperoxia is rather consistently patients-an observational cohort study. Anaesth Intensive Care. 2013;41:505-14. associated with adverse outcome and should be avoided, optimal 21. Mikkelsen ME, Anderson B, Christie JD, Hopkins RO, Lanken PN. Can We Optimize Long-Term Outcomes in Acute Respiratory Distress Syndrome by Targeting oxygenation targets in ICU patients remain to be determined. Normoxemia? Ann Am Thorac Soc. 2014;11:613-8. Some observational studies have shown beneficial effects of mild 22. Helmerhorst HJF, Schouten LRA, Wagenaar GTM, et al. Hyperoxia provokes a time- and dose-dependent inflammatory response in mechanically ventilated to moderate hyperoxia suggesting that optimal targets might not mice, irrespective of tidal volumes. Intensive Care Med Exp. 2017;5:27.

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Editorial board of the Netherlands Journal of Critical Care Nicole Juffermans, Editor in Chief Janneke Horn, Section Editor Marike van der Schaaf, Section Pieter Roel Tuinman, Section Dept. of Intensive Care General Editor Rehabilitation Editor General Academic Medical Center Dept. of Intensive Care Dept. of Rehabilitation Dept. of Intensive Care Medicine University of Amsterdam Academic Medical Center Academic Medical Center VU University Medical Center Meibergdreef 9 University of Amsterdam University of Amsterdam PO Box 7057 1105 AZ Amsterdam Meibergdreef 9 Meibergdreef 9 1007 MB Amsterdam 1105 AZ Amsterdam 1105 AZ Amsterdam Walter van den Bergh, Section Alexander Vlaar, Section Editor Editor General Leo Heunks, Section Editor Arjen Slooter, Section Editor General Dept. of Critical Care Mechanical ventilation Mental health Dept. of Intensive Care University of Groningen Dept. of Critical Care Medicine Dept. of Intensive Care Academic Medical Center Hanzeplein 1 Radboud University Nijmegen University Medical Center Utrecht University of Amsterdam 9700 RB Groningen Medical Center PO Box 85500 Meibergdreef 9 PO Box 9101 3508 GA Utrecht 1105 AZ Amsterdam Dennis Bergmans, Section Editor 6500 HB Nijmegen Infection and Inflammation Peter Spronk, Associate Editor David van Westerloo, Section Dept. of Intensive Care Can Ince, Section Editor Physiology General Editor General Maastricht University Medical Dept. of Physiology Dept. of Intensive Care Medicine Dept. of Intensive Care Medicine Center+ Academic Medical Center Gelre Hospital, location Lukas Leiden University Medical Center P. Debyelaan 25 University of Amsterdam PO Box 9014 PO Box 9600 6229 HX Maastricht Meibergdreef 9 7300 DS Apeldoorn 2300 RC Leiden 1105 AZ Amsterdam Frank Bosch, Section Editor Ilse van Stijn, Managing Editor Job van Woensel, Section Editor Imaging Evert de Jonge, Section Editor Dept. of Intensive Care Medicine Pediatrics Dept. of Internal Medicine Scoring and quality assessment Onze Lieve Vrouwe Gasthuis Pediatrics Intensive Care Unit Rijnstate Hospital Dept. of Intensive Care Medicine PO Box 95500 Emma children’s hospital PO Box 9555 Leiden University Medical Center 1090 HM Amsterdam Academic Medical Center 6800 TA Arnhem PO Box 9600 University of Amsterdam Eleonora Swart, Section Editor 2300 RC Leiden Meibergdreef 9 Diederik van Dijk, Section Editor Pharmacology 1105 AZ Amsterdam Cardioanesthesia Michael Kuiper, Associate Editor Dept. of Pharmacy Dept. of Intensive Care Medicine, Neurology Academic Medical Centre Div. of Anesthesiology, Intensive Dept. of Intensive Care Medicine University of Amsterdam Care and Emergency Medicine Medical Center Leeuwarden Meibergdreef 9 University Medical Center Utrecht PO Box 888 1105 AZ Amsterdam PO Box 85500 8901 BR Leeuwarden Dept. of Clinical Pharmacology and 3508 GA Utrecht Pharmacy Matijs van Meurs, Section Editor VU University Medical Center Dirk Donker, Section Editor Anesthesiology De Boelelaan 1117 Cardiology Dept. of Critical Care 1081 HV Amsterdam Dept. of Intensive Care Medicine, University of Groningen Div. of Anesthesiology, Intensive Hanzeplein 1 Care and Emergency Medicine 9700 RB Groningen University Medical Center Utrecht PO Box 85500 3508 GA Utrecht

International advisory board Jan Bakker Charles Hinds Paul Marik Xavier Monnet Professor of Intensive Care Professor of Intensive Care Associate Professor Service de réanimation médicale Columbia University Medical Medicine Dept. of Medicine and Medical Centre Hospitalier Universitaire Center, New York University St. Bartholomew’s Hospital Intensive Care Unit de Bicêtre Medical Center, New York, USA West Smithfield, University of Massachusetts Le Kremlin-Bicêtre, France Pontificia Universidad Católica de London, UK St. Vincent’s Hospital, Jean-Charles Preiser Chile, Santiago, Chile Worcester, USA Patrick Honoré Dept. Intensive Care Erasmus MC University Medical Professor of ICU Medicine Greg Martin Erasme University Hospital Center, Rotterdam, Netherlands Director of Critical Care Dept. of Medicine Brussels, Belgium Charles Gomersall Nephrology Platform Division of Pulmonary, Allergy and Yasser Sakr Dept. of Anaesthesia and Intensive ICU department Critical Care Dept. of Anaesthesiology and Care Universitair Ziekenhuis Brussel, Emory University School of Intensive Care The Chinese University of Hong VUB University Medicine Friedrich-Schiller University Kong, Prince of Wales Hospital Brussels, Belgium Atlanta, USA Hospital Hong Kong, China Alun Hughes Ravindra Mehta Jena, Germany Frank van Haren Professor of Clinical Pharmacology Professor of Clinical Medicine Hannah Wunsch A/ Professor, Australian National University College London Associate Chair for Clinical Dept. of Anaesthesia University Medical School London, UK Research New York Presbyterian Columbia Department of Intensive Care Department of Medicine Manu Malbrain New York, USA Medicine UCSD Medical Centre Dept. of Intensive Care Unit The Canberra Hospital San Diego, USA Hospital Netwerk Antwerp PO Box 11, Woden, ACT 2606 Campus Stuivenberg Canberra, Australia Antwerp, Belgium

NETH J CRIT CARE - VOLUME 26 - NO 2 - MARCH 2018 89 Netherlands Journal of Critical Care

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Authors wishing to include figures or tables that have APACHE acute physiology and chronic health evaluation already been published elsewhere are required to obtain permission from the BIPAP biphasic positive airways pressure copyright owner and provide evidence that such permission has been granted CCU coronary care unit when submitting their paper. Colour figures can be published. Short, clear COPD chronic obstructive pulmonary disease legends make additional description in the text unnecessary. Figures should be CPAP continuous positive airway pressure provided in electronic format (TIFF or JPEG). CT computed tomography ECG electrocardiogram Conflict of interest ECMO extracorporeal membrane oxygenation Authors must indicate any conflict of interest. This includes a financial EEG Electroencephalogram relationship with an organisation that sponsored the research (funding, ELISA enzyme-linked immunosorbent assay speakers fee, consultancy fee), management relations with the organisation that ETCO2 end-tidal carbon dioxide sponsored the research (consultant, member of board). All sources of funding HIV human immunodeficiency virus obtained for the research should also be stated. A conflict of interest statement IC intensive care can be downloaded from the website. The completed and signed form should ICU intensive care unit be uploaded as a separate document when submitting the manuscript. If no IM Intramuscular conflict exists, authors should state: All authors declare no conflicts of interest. INR international normalised ratio IPPV intermittent positive pressure ventilation No funding or financial support was received. IV Intravenous Author agreement MAP mean arterial pressure MODS multiorgan dysfunction syndrome All authors must certify they have seen and approved the manuscript being MRI magnetic resonance imaging submitted. All authors warrant that the article is the authors’ original work, has PACU post anaesthesia care unit not been published previously and is not under consideration for publication PEEP positive end expiratory pressure elsewhere. The author agreement form can be downloaded from the website. An PET positron emission tomography article will only be published when this form is completed, signed and returned. SARS severe adult respiratory syndrome SIRS systemic inflammatory response syndrome Copyright SOFA sequential organ failure assessment Copyright ownership is to be transferred in a written statement, which must SPECT single-photon emission computed tomography accompany all manuscript submissions and must be signed by all authors. TIA transient ischaemic attack The agreement should state: ‘The undersigned authors transfer all copyright TRALI transfusion-related acute lung injury

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