Massimo AntonelliElie AzoulayMarc BontenJean ChastreGiuseppe CiterioGiorgio ContiDaniel De BackerHerwig GerlachGoran HedenstiernaMichael JoannidisDuncan MacraeJordi ManceboSalvatore M. MaggioreAlexandre MebazaaJean-Charles PreiserJerome PuginJan WernermanHaibo Zhang

Year in review in Intensive Care Medicine2010: III. ARDS and ALI, mechanicalventilation, noninvasive ventilation, weaning,endotracheal intubation, lung ultrasoundand paediatrics

Received: 19 January 2011Accepted: 19 January 2011Published online: 3 February 2011� Copyright jointly held by Springer andESICM 2011

M. Antonelli ()) � G. Conti �S. M. MaggioreDepartment of Intensive Care andAnesthesiology, Policlinico UniversitarioA. Gemelli, Universita Cattolica del SacroCuore, Largo A. Gemelli, 8,00168 Rome, Italye-mail: m.antonelli@rm.unicatt.itTel.: ?39-06-30153226;

?39-06-30154386

E. AzoulayIntensive Care Medicine Unit,Saint Louis Hospital, Paris, France

M. BontenDepartment of Medical Microbiology,Julius Center for Health Sciences andPrimary Care University Medical Center,Utrecht, The Netherlands

J. ChastreReanimation medicale, Hopital PitieSalpetriere, Paris, France

G. CiterioNeurointensive Care Unit, Ospedale S.Gerardo, Monza, Italy

D. De BackerService des Soins Intensifs,Erasme Hospital, Brussels, Belgium

H. GerlachDepartment of Anesthesiology,Vivantes-Klinikum Neukoelln,Berlin, Germany

G. HedenstiernaDepartment of Clinical Physiology,Uppsala University, Uppsala, Sweden

M. JoannidisDepartment of Internal Medicine,Medical University of Innsbruck,Innsbruck, Austria

D. MacraePediatric Intensive Care Unit,Royal Brompton Hospital,London, UK

J. ManceboIntensive Care Medicine Unit,Hospital Sant Pau, Barcelona, Spain

A. MebazaaDepartment of Anesthesiology and CriticalCare Medicine, Lariboisiere Hospital,Paris, France

J.-C. PreiserDepartment of Intensive Care,Erasme University Hospital,Brussels, Belgium

J. PuginIntensive Care Medicine Unit,University Hospital of Geneva,Geneva, Switzerland

J. WernermanDepartments of Anesthesiology andIntensive Care Medicine,Karolinska University Hospital,Stockholm, Sweden

H. ZhangInterdepartmental Division of Critical CareMedicine, University of Toronto,Toronto, Canada

ARDS and ALI

In an observational, 4-month study performed in a refer-ence centre in France, Roch et al. [1] compared

characteristics, clinical evolution and outcome of adultpatients with acute respiratory distress syndrome (ARDS)associated with influenza A (H1N1), treated with (ninepatients) or without (nine patients) extracorporeal

Intensive Care Med (2011) 37:394–410DOI 10.1007/s00134-011-2136-1 YEAR IN REVIEW 2010

membrane oxygenation (ECMO). Before ECMO, patientshad refractory respiratory failure (PaO2/FiO2 52 mmHg,PaCO2 85 mmHg). Six ECMO treatments were initiatedin the referral hospital by a mobile team. Patients treatedwith or without ECMO had the same hospital mortalityrate (56%). Duration of ECMO therapy was longer insurvivors than in non-survivors (9 vs. 5 days). AfterECMO initiation, early improvement of PaO2/FiO2 wasgreater in survivors than in non-survivors. Haemorrhagiccomplications occurred in 44% of ECMO patients, butnone required surgical treatment. The conclusion was thatECMO may be an effective salvage treatment for patientswith influenza A (H1N1)-related ARDS presenting rapidrefractory respiratory failure, particularly when providedearly in a specialized reference centre.

In an accurate meta-analysis Sud et al. [2] analysed theeffects of prone versus supine ventilation in acute hyp-oxaemic respiratory failure (AHRF) and severehypoxaemia (PaO2/FiO2 \ 100 mmHg) compared withmoderate hypoxemia (PaO2/FiO2 between 100 and300 mmHg). Ten trials (N = 1,867 patients) met inclu-sion criteria; most patients had acute lung injury.Methodological quality was relatively high. Prone venti-lation reduced mortality in patients with PaO2/FiO2 below100 mmHg [risk ratio (RR) 0.84, 95% confidence interval(CI) 0.74–0.96; p = 0.01; seven trials, N = 555] but notin patients with PaO2/FiO2 equal to or higher than100 mmHg (RR 1.07, 95% CI 0.93–1.22; p = 0.36; seventrials, N = 1,169). Post hoc analysis demonstrated sta-tistically significant improved mortality in the morehypoxaemic subgroup and significant differences betweensubgroups using a range of PaO2/FiO2 thresholds up toapproximately 140 mmHg. Prone ventilation improvedoxygenation by 27–39% over the first 3 days of therapybut increased the risks of pressure ulcers (RR 1.29, 95%CI 1.16–1.44), endotracheal tube obstruction (RR 1.58,95% CI 1.24–2.01) and chest tube dislodgement (RR3.14, 95% CI 1.02–9.69). The authors concluded thatprone ventilation reduces mortality in patients with severehypoxaemia, but given the associated risks, the proneposition should not be routine in all patients with AHRF,but may be considered for severely hypoxaemic patients.

Laminin-5, a cell adhesive molecule expressed solelyby the epithelium, is known to enhance epithelial cellmigration and repair of the injured epithelium. Its physi-ological role in alveolar epithelial injury remainsunknown. The terminal gamma 2 fragment (G2F) oflaminin-5 can be detected in the peripheral blood. Ka-tayama et al. [3] examined the relationship betweendisease status and alveolar laminin-5 accumulation duringthe exudative phase in patients with acute lung injury(ALI), as reflected by circulating G2F levels. Sampling ofepithelial lining fluids or pulmonary edema fluids frompatients with acute lung injury ALI or related diseaseswas performed. Plasma samples were obtained from themat the time of disease onset or later. The authors found a

significantly higher amount of G2F in pulmonary edemaand epithelial lining fluids of patients with ALI, as com-pared with those with the other respiratory diseases. Theplasma levels were also elevated significantly early at theonset of ALI (mean ± SD, 147 ± 82 ng/ml in non-sur-viving and 90 ± 56 in surviving patients) as comparedwith those in the patients with cardiogenic pulmonaryedema (59 ± 36) or idiopathic pulmonary fibrosis(37 ± 17). At 5 days after onset, non-surviving patientsmaintained higher plasma concentrations (152 ± 84), butin contrast, the levels in surviving patients declined(71 ± 35), suggesting secretion of laminin-5 was sup-pressed, associated with recovery from ALI. It wasconcluded that circulating G2F may be a useful biomarkerto monitor the pneumocyte re-epithelialization processduring alveolar repair in ALI patients.

Pulmonary hypertension is a characteristic feature ofARDS and contributes to mortality. Phosphodiesterases(PDE) inactivate cyclic GMP and thus relaxation ofsmooth muscle cell is inhibited. Cornet et al. [4] con-ducted a study to investigate whether sildenafil, whichselectively inhibits the isoenzyme PDE5, is beneficial forpatients with ARDS. Ten consecutive ARDS patientsreceived a single dose of 50 mg sildenafil via a naso-gastric tube. Sildenafil decreased mean pulmonary arterialpressure from 25 to 22 mmHg (p = 0.022) and pulmon-ary artery occlusion pressure from 16 to 13 mmHg(p = 0.049). Systemic mean arterial pressures weremarkedly decreased from 81 to 75 mmHg (p = 0.005).Sildenafil did not improve pulmonary arterial oxygentension, but resulted in a further increase in the shuntfraction. It was concluded that the results did not justify aroutine place for sildenafil in the treatment of ARDSpatients. This article was accompanied by an editorial [5].

Transfusion of blood components is common inpatients admitted to the intensive care unit (ICU) forgastrointestinal (GI) bleeding. However, the incidenceand risk factors for development of transfusion-relatedacute lung injury (TRALI) in these patients are unknown.Data on 255 patients admitted to a medical ICU for GIbleeding and with specific risk factors for development ofTRALI were analysed in a paper published in the Octoberissue [6]. In transfused patients (n = 150), the incidenceof TRALI was 15% and accounted for 76% (22/29) of allALI cases. Transfused patients with end-stage liver dis-ease (ESLD; n = 72) developed TRALI more frequentlythan those without ESLD (29 vs. 1%, p \ 0.01). Freshfrozen plasma (FFP) was temporally associated withTRALI in 86% of cases. Transfusion-specific risk factorsfor development of TRALI included number of transfusedunits of FFP and non-leukoreduced red blood cells.Patient-specific risk factors included model for ESLDscore, admission serum albumin level, and presence ofALI risk factors. It was concluded that TRALI is commonin critically ill ESLD patients with GI bleeding. Non-leukoreduced red blood cells and FFP are significant

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transfusion-specific risk factors and their use should be re-evaluated in these patients.

Acute respiratory failure might be a cause of ICUadmission of pregnant and postpartum women. A sys-tematic review of studies reporting the incidence andcharacteristics of these patients was published in theSeptember issue [7]. A total of 40 eligible studiesreporting outcomes for 7,887 women were analysed. Allstudies were retrospective with the majority reporting datafrom a single centre. The incidence of ICU admissionranged from 0.7 to 13.5 per 1,000 deliveries. Pregnant orpostpartum women accounted for 0.4–16.0% of ICUadmissions. Hypertensive disorders with acute respiratoryfailure were the most prevalent indication for ICUadmission [median 0.9 cases per 1,000 deliveries (range0.2–6.7)]. There was no difference in the profile of ICUadmission in developing compared to developed coun-tries, except for the significantly higher maternalmortality rate in developing countries (median 3.3 vs.14.0%, p = 0.002). Studies reporting patient outcomessubsequent to ICU admission are lacking. Pollock et al.[7] concluded that ICU admission of pregnant and post-partum women occurs infrequently. The ICU admissionprofile of women was similar in developed and develop-ing countries; however, the maternal mortality rateremains higher for ICUs in developing countries. The ICUadmission is potentially a useful indicator of severematernal morbidity that captures data on women with themost severe disease.

Clinical applications of quantitative computedtomography (qCT) in patients with pulmonary opacitiesand ARDS are important, but are hindered by the radia-tion exposure and by the arduous manual imageprocessing. Reske et al. [8] hypothesized that extrapola-tion from only ten thoracic CT sections will providereliable information about the aeration of the entire lung.A retrospective analysis of CTs of 72 patients with normaland 85 patients with opacified lungs was done. Volumesand masses of the lung and its differently aerated com-partments were obtained from all CT sections. Then onlythe most cranial and caudal sections and a further eightevenly spaced sections between them were selected. Theresults from these ten sections were extrapolated to theentire lung. The median (range) total lung volume was3,738 (1,311–6,768) ml, and the 95% limits of agreementwere 26 (-42 to 95) ml. The median volumes (range) ofdifferently aerated compartments (percentage of total lungvolume) were 1 (0–54)% for the non-aerated, 5 (1–44)%for the poorly aerated, 85 (28–98)% for the normallyaerated and 4 (0–48)% for the hyperaerated compartment.The agreement between the extrapolated results and thosefrom all CT sections was excellent: the limits of agree-ment never exceeded ±2%. It was concluded that theextrapolation method can reduce radiation exposure andshorten the time required for qCT analysis of lung aera-tion and thus foster the application of the technique into

research and clinical practice. This article has an editorialcomment [9].

Giraud and co-workers [10] tested whether the moni-toring of transpulmonary thermodilution curves can beused for detecting shunt. It is an interesting approach inwhich the authors tried to detect a vascular shunt betweenthe arterial and venous side in the systemic circulation.Such shunt causes an early recirculation of the indicator.As a result of the low signal to noise ratio it can bedifficult to detect early recirculation of the thermal indi-cator but it will also have an effect on the calculation ofextravascular lung water (reflecting lung edema). Bymeasuring obviously overestimated lung water, attentionshould be paid to the possible presence of a circulatoryshunt (arteriovenous fistula?).

Mechanical ventilation

Ventilator performances and patient–ventilatorinteraction

Two studies evaluated performances of modern mechan-ical ventilators in specific conditions. In a bench study,Lyazidi et al. [11] assessed the performance of algorithmsused by nine ICU ventilators to compensate for the vol-ume compressed into the circuit and evaluated theaccuracy of tidal volume delivered during volume-con-trolled ventilation. Measurements were performed underdifferent conditions of respiratory mechanics, taking alsointo account humidity and temperature of the deliveredgas. Delivered volume differed significantly across ven-tilators with an error range of -15 to 32% for set tidalvolume, which represents 1–2 ml/kg for a preset tidalvolume of 6 ml/kg predicted body weight. Respiratorysystem mechanics and application of an inspiratory pausesignificantly affected tidal volume actually delivered.Lyazidi et al. concluded that the difference between presettidal volume and volume actually delivered is clinicallymeaningful and differs across modern ICU ventilators. Ina multicentre randomized cross-over study, Vignaux et al.[12] evaluated the impact of noninvasive ventilation(NIV) algorithms available on modern ICU ventilators onthe incidence of patient–ventilator asynchrony in 65patients with acute respiratory failure. Although overallasynchrony was unchanged, the mean number of asyn-chronies influenced by leaks was significantly reduced byactivating the NIV mode (from 28 to 12% without andwith the NIV algorithm, respectively). In particular,ineffective efforts and late cycling significantlydecreased, but some NIV algorithms tended to promotepremature cycling. In conclusion, NIV algorithms pro-vided by ICU ventilators can reduce the incidence of leak-associated asynchronies, while not necessarily changingthe overall asynchrony.

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A new device, the PVI monitor, has been proposed tomonitor and improve patient–ventilator interaction [13].This device can calculate the patient’s total inspiratorymuscle pressure using estimated values of resistance andelastance of the respiratory system. Kondili et al. [14]evaluated the accuracy of the new device to quantifyinspiratory muscle pressure by comparing values of totalinspiratory muscle pressure measured using the trans-diaphragmatic/esophageal pressure to those calculated bythe PVI monitor in 11 patients ventilated with propor-tional assist ventilation plus. Values of inspiratory musclepressure and inspiratory and expiratory time did not differamong the various methods of calculation. Inspiratorymuscle pressure decreased with increasing the level ofventilator assistance, and the magnitude of this decreasedid not differ among the various methods. Kondili et al.concluded that the PVI monitor may be used to providebreath-by-breath quantitative information about inspira-tory muscle pressure in mechanically ventilated patients.

Synchrony between patient and ventilator stronglydepends on settings and interfaces. Costa et al. [15]evaluated patient–ventilator interaction during pressuresupport ventilation (PSV) delivered with three interfaces:endotracheal tube (ET), face mask (FM) and helmet (H).The study was performed at different pressurization times(Time (press)), cycling-off flow thresholds (Tr (exp)) andrespiratory rates in a bench study, and with FM and H in ahealthy volunteers study. PSV was delivered through thethree interfaces with three different respiratory rates in thebench study, and through FM and H at two differentrespiratory rates in the human study. The tested ventilatorsettings expressed as Time (press)/Tr (exp) were 50%/25% (default setting), 20%/5% (slow setting) and 80%/60% (fast setting). The patient–ventilator synchrony wassignificantly better with ET, with significantly lowerinspiratory trigger delay and significantly higher time ofassistance. The slow setting at respiratory rates of 30breaths per minute produced the worst interaction, withhigher rates of wasted efforts compared with the fastsetting (20, 40 and 50% of wasted efforts versus 0, 16 and26% of all spontaneous breaths, with ET, FM and H,respectively; p \ 0.01). In both studies the FM resulted inbetter synchrony as compared with the H. It was con-cluded that patient–ventilator synchrony was significantlybetter with the ET than with the FM or H in the benchstudy. In vivo, the FM outperformed the H and fast set-tings can correct some of the limitations in terms ofsynchrony.

Modes of ventilation

Bilevel positive airway pressure ventilators, commonlyemployed to deliver NIV, use single-limb tubing whichcan increase the amount of CO2 rebreathing. Szkulmow-ski et al. [16] measured the amount of rebreathing with

such ventilator circuits and assessed predictive factors forCO2 re-inhalation in patients receiving PSV, eitherthrough an endotracheal tube or with a NIV mask. Only19% of the measured cycles had an inspired fraction ofCO2 greater than 0.1%. Four parameters were able topredict CO2 rebreathing: high end-tidal CO2, low positiveend-expiratory pressure (PEEP), intubation and highrespiratory rate. These results suggest that the risk ofrebreathing with bilevel ventilators in the clinical settingis modest; application of PEEP and avoidance of highrespiratory rates can further decrease this risk.

Several studies evaluated new ventilatory modes andtechniques. Isgro et al. [17] described a new continuouspositive airway pressure (CPAP) system equipped with anelectromechanical expiratory valve designed to switchbetween two PEEP levels on a time-cycled basis. Byusing such a device, the authors investigated the effectson oxygenation of applying a sigh (2 high pressurebreaths per minute) or a biphasic positive pressure ven-tilation (10 mandatory breaths per minute) in patientswith hypoxic respiratory failure undergoing continuousflow CPAP with a helmet. As compared with CPAPalone, the application of periodic sighs and biphasicpositive airway pressure (BIPAP) induced a similarimprovement in oxygenation which was maintained for atleast 1 h after returning to standard CPAP. Isgro et al.concluded that periodic, non-synchronized higher pres-sure breaths delivered at a rate as low as 2 breaths/minmay improve oxygenation during helmet CPAP in hyp-oxaemic patients. Iotti et al. [18] reported the results of amulticentre, crossover trial performed to assess the short-term effects of adaptive support ventilation (ASV) ascompared with conventional volume or pressure-controlventilation in 88 patients with acute respiratory failureundergoing total ventilatory support. As compared withconventional ventilation and at the same minute ventila-tion, ASV resulted in a slightly lower PaCO2 withoutchanges in oxygenation. During ASV, respiratory ratewas slightly lower and tidal volume slightly greater thanconventional ventilatory modes, especially in patientswith obstructive disease. The ventilatory patterns selectedby ASV were similar to those chosen by the cliniciansduring conventional ventilation: tidal volume was lowerin patients with restrictive disease and expiratory timewas prolonged in obstructed patients. With ASV, tidalvolume was, however, unacceptably high in 11% ofchronic obstructive pulmonary disease patients. Iotti et al.concluded that, as compared with conventional ventila-tion, ASV resulted in a similar ventilatory pattern and, in35% of patients, in a more efficient CO2 elimination.Gonzalez et al. [19] performed a case-matched analysisaccording to a propensity score to compare characteristicsand clinical outcomes of 234 patients receiving airwaypressure release ventilation (APRV) or BIPAP with thoseof 1,228 patients ventilated with assist-control ventilation(A/C) only. APRV/BIPAP was used only in selected

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geographic areas (84% patients in Germany). Patientswere less likely to be ventilated with APRV/BIPAP in thecase of coma or congestive heart failure, pH \ 7.15 priorto mechanical ventilation, and respiratory failure devel-oping after intubation. No differences in clinicaloutcomes were observed between groups.

A novel adaptive control system for noisy pressure-controlled ventilation was proposed in ‘‘a numericalsimulation and bench test study’’ by Gama de Abreu’sresearch group [20]. They developed and evaluated acontrol system based on the least-mean-squares adaptiveapproach that enables an automatic and continuousadjustment of the driving pressure during pressure-con-trolled ventilation to achieve desired variability in thetidal volume. Their conclusion is that the control systemworks under model experimental conditions, which isobviously a step before the clinical testing. It should beemphasized that the same group has demonstrated anumber of advantages using noisy ventilation withimproved respiratory mechanics and gas exchange.

ECMO can support oxygenation and carbon dioxideelimination in severe lung failure. Usually it is accom-panied by controlled mechanical ventilation. Neurallyadjusted ventilatory assist (NAVA) may allow a closeinteraction between ventilation and extracorporeal perfu-sion. In a pilot study, Karagiannidis et al. [21] intended tomeasure the physiologic ventilatory response in patientswith severe lung failure treated with ECMO and NAVA.The authors hypothesized that the combination of bothmethods could automatically provide a protective venti-lation with optimized blood gases. A case series of sixpatients treated with ECMO for severe lung failure isdescribed. Tidal volumes on ECMO ranged between 2and 5 ml/kg predicted body weight and increased up to8 ml/kg with inactivated ECMO. Ventilatory response todecreased sweep gas flow was rapid, and patients imme-diately regulated PaCO2 tightly towards a physiologicalpH value. Increase in minute ventilation was a result ofincreased breathing frequency and tidal volumes. It wasconcluded that combination of NAVA and ECMO maypermit a closed-loop ventilation with automated protec-tive ventilation.

High-frequency oscillation (HFO) and tracheal gasinsufflation (TGI) are employed in patients with ALI/ARDS to enhance oxygenation and CO2 elimination.Mentzelopoulos et al. [22] compared HFO with andwithout TGI at the same mean tracheal pressure, to assesswhether TGI can improve gas exchange independentlyfrom tracheal pressure. Two levels of mean trachealpressure were studied. HFO with TGI resulted in betteroxygenation (at both mean tracheal pressures) and lowerPaCO2 (at the higher level of tracheal pressure) than HFOalone. The authors concluded that, at equal level of tra-cheal pressure, combining HFO with TGI resulted inbetter gas exchange than standard HFO. High-frequencypercussive ventilation (HFPV) has been suggested to be

beneficial in ARDS patients. Lucangelo et al. [23] per-formed a bench study in a bicompartmental mechanicallung model to assess whether and how varying theresistive and elastic loads applied to one compartmentonly would modify gas distribution between the twopathways under HFPV and pressure-controlled ventila-tion. With HFPV, hyperinflation was prevented and tidalvolume was reduced. Gas distribution between the twocompartments differed according to the ventilatory mode:unlike pressure-controlled ventilation, gas distributionwith HFPV was not determined by the time constant ofeach compartment. In conclusion, HFPV accommodatedvolume distribution without overinflating compartmentswith low time constants, thus possibly presenting apotential protective behaviour in mechanically heteroge-neous lungs.

Noninvasive ventilation

Several studies were dedicated to NIV. Phua et al. [24]evaluated the role of NIV in acute respiratory failureassociated with bronchiectasis: the authors retrospectivelyreviewed bronchiectatic patients placed on NIV (n = 31)or invasive mechanical ventilation (IMV; n = 26) foracute respiratory failure over 8 years. At baseline, theNIV group had more patients with acute exacerbationswithout identified precipitating factors (87.1 vs. 34.6%),higher pH (mean 7.25 vs. 7.18) and PaO2/FiO2 ratio(mean 249.4 vs. 173.2, p = 0.02), and a trend towards alower APACHE II score than the IMV group. There wasno difference in hospital mortality between the twogroups (25.8 vs. 26.9%, p [ 0.05). The NIV failure ratewas 32.3%. Using logistic regression, Phua et al. foundthat the APACHE II score was the only predictor ofhospital mortality, and the PaO2/FiO2 ratio was the onlypredictor of NIV failure.

The possible role of small dead space heat and mois-ture exchangers (HME) during NIV was assessed incomparison with a heated humidifier (HH) [25]. Theeffects of HME and HH on respiratory rate, minute ven-tilation, EtCO2, oxygen saturation, airway occlusionpressure at 0.1 s, arterial blood gases (ABG), and comfortperception were compared during two randomly deter-mined NIV periods of 30 min. No difference wasobserved between HME and HH suggesting that if onedecides to humidify patients’ airways during NIV, onemay do so with small dead space HME or HH withoutaltering respiratory parameters.

Fartoukh et al. [26] evaluated the use of early inter-mittent NIV for acute chest syndrome (ACS) in adultswith sickle cell disease in a pilot study. Seventy-oneconsecutive ACS episodes in 67 patients were randomlyallocated to oxygen (n = 36) or NIV (n = 35) for 3 daysin a medical step-down unit. Baseline respiratory rate and

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pain score were higher in the NIV group. NIV promptlylowered the respiratory rate, raised PaO2, and decreasedalveolar–arterial oxygen gradient (A-a)O2, whichremained unchanged with oxygen alone. PaCO2 signifi-cantly worsened only in the oxygen group. On day 3, thegroups did not differ regarding the proportion of episodeswith normal PaO2. In the subgroup of patients with severehypoxaemia, physiological variables also improved fasterwith NIV.

The use of NIV for diagnostic bronchoscopy using anew face mask was evaluated by Heunks et al. [27]. Acommercially available full-face mask was modified toallow introduction of the bronchoscope without interfer-ing with the ventilator circuit. Bronchoscopy withbronchoalveolar lavage was performed in 12 hypoxaemicnon-ICU patients during NIV in the ICU. Oxygenationimproved after initiation of noninvasive positive pressureventilation. In all patients the procedure could be com-pleted without subsequent complications, although in onepatient SpO2 decreased until 86% during bronchoscopy.A microbiological diagnosis could be established in 8 of12 patients with suspected infection.

The problem of sedation during NIV was evaluated byClouzeau et al. [28] studying the use of target-controlledinfusion (TCI) of propofol for sedation in patients withnoninvasive ventilation failure due to low tolerance. Tenpatients with NIV failure due to discomfort, agitation and/or refusal to continue with this ventilatory support wereincluded; seven had acute respiratory failure and threehad acute hypercapnic respiratory failure. Patients weresedated by TCI of propofol during NIV sessions. Bloodgas analysis, cardiorespiratory and ventilatory parameters,propofol concentration (Cpt) required, comfort andadverse events were recorded. NIV under TCI of propofolsignificantly improved arterial blood gas analyses; threepatients required endotracheal intubation, two due toevolution of underlying disease and one because of aseizure disorder. Eight patients were discharged from theICU and two died, suggesting that in a selected popula-tion, TCI of propofol can facilitate acceptance of NIV.

Mask intolerance and discomfort are factors related toNIV failure. Analgesia-based sedation has been proposedto manage NIV failure in patients with acute respiratoryfailure. Rocco et al. [29] aimed to assess the feasibility ofremifentanil-based sedation in hypoxaemic acute respi-ratory failure (HARF) patients refusing to continue NIVfor intolerance to two different interfaces: helmet andtotal face mask. Thirty-six patients with persistent severeHARF who complained of discomfort and asked forinterruption of NIV session were prospectively studied.Patients started sedation with remifentanil (0.025 lg/kg/min/kg) and the infusion rate was increased by 0.01 lg/kg/min every minute to a maximum of 0.12 lg/kg/min toobtain patient comfort. Twenty-two out of 36 patients(61%) continued the NIV treatment after the introductionof remifentanil infusion. In this success group, median

(interquartile range, IQR) respiratory rate decreased from34 (31, 37) to 24 (20, 26) per min (p \ 0.0001) and PaO2/FiO2 ratio increased from 156 (144, 176) to 270 (210,300) mmHg (p \ 0.0001) after 1 h of NIV with remif-entanil, either with a helmet or total face mask. Fourteenpatients failed to continue NIV and were intubated after amean of 2.5 ± 2.3 h; they showed a respiratory ratedecrease from 35 (30, 38) to 27 (25, 35) per min(p = 0.02) and an inability to increase the PaO2/FiO2

ratio above 180 mmHg. The ICU mortality in the failuregroup patients was 50 versus 14% in the NIV successgroup (p \ 0.05). It was concluded that a remifentanil-based sedation strategy is feasible and safe.

Continuous positive airway pressure ventilation with ahelmet was evaluated in infants under 1 year by Milesiet al. [30]. Twenty-three infants with a median age of 5(2–8) months were included. Helmet CPAP failed in two(9%) patients. Stability or improvement occurred in 16(70%) patients. The pain and discomfort score was stableor improved in 22 (96%). The authors concluded that thehelmet was a satisfactory interface for CPAP delivery inyoung infants in more than two-thirds of the cases.

Weaning

Optimal weaning strategy was assessed by Cabello et al.[31] in a physiological comparison of three spontaneousbreathing trials (SBTs) in difficult-to-wean patients. Thestudy aim was to compare cardiovascular and respiratoryresponses to different SBTs in difficult-to-wean patientsusing T-piece and pressure support ventilation (PSV) withor without PEEP. Fourteen patients who were monitoredwith a Swan–Ganz catheter and had failed a previousT-piece trial were studied. Three SBTs were performed inrandom order in all patients: PSV with PEEP (PSV-PEEP), PSV without PEEP (PSV-ZEEP), and T-piece.PSV level was 7 cmH2O, and PEEP was 5 cmH2O. Mostpatients succeeded in the PSV-PEEP (11/14) and PSV-ZEEP (8/14) trials, but all failed the T-piece trial. Patienteffort was significantly higher during T-piece than duringPSV with or without PEEP. Left ventricular heart failurewas observed in 11 of the 14 patients during the T-piecetrial. Pulmonary artery occlusion pressure and respiratoryrate were significantly higher during T-piece than withPSV-PEEP and tidal volume was significantly lowerduring the T-piece trial. The authors’ conclusion was thatin a population of difficult-to-wean patients, PSV andPSV plus PEEP markedly modified the breathing pattern,inspiratory muscle effort, and cardiovascular response ascompared with the T-piece. Rapid shallow breathing mayoccur at any time during SBTs, questioning the utility of asingle determination of the rapid shallow breathing index(RSBI). Segal et al. [32] hypothesized that change inRSBI during SBT may more accurately predict successful

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extubation than RSBI determination at a point in time.The percent change in RSBI during a 2-h SBT in indi-vidual subjects was evaluated in a prospective manner.Seventy-two subjects were extubated. At 24 h, 63/72remained extubated (Extubation Success), and 9 were re-intubated (Extubation Failure). Respiratory rate, tidalvolume (VT) and RSBI were measured every 30 minduring the 2-h T-piece SBT. Initial RSBI was similar inExtubation Success and Extubation Failure groups(77.0 ± 4.8, 77.0 ± 4.8, p = not significant), and RSBItended to remain unchanged or decreased in the Extuba-tion Success group. However, RSBI tended to increase inthe Extubation Failure group because of either increasedrespiratory rate and/or decreased VT (p \ 0.001 for meanpercent change RSBI over time). Only 7/63 subjects ofthe Extubation Success group demonstrated increasedRSBI C 20% at any time during the SBT. In contrast, inthe Extubation Failure group, RSBI increased in all subjectsduring the SBT, and eight of nine subjects demonstrated anincrease greater than 20%. Thus, with a 2-h SBT the optimalthreshold was a 20% increase (sensitivity = 89%, specific-ity = 89%). Percent change of RSBI predicted successfulextubation even when initial values were C105. Segal et al.concluded that the change in RSBI is a marker of dynamicchanges that occur during weaning that may improve theability to predict extubation outcome.

The SBT relies on objective criteria assessed by theclinician. However, little is known regarding the patient’ssubjective perception of autonomous breathing. A pro-spective observational study in 211 mechanicallyventilated adult patients successfully completing a SBTanalysed this specific subject [33]. Patients were ran-domly assigned to be interviewed during this trialregarding their prediction of extubation success. The post-extubation outcomes were compared in three patientgroups: patients confident (confidents; n = 115) or not(non-confidents; n = 38) of their extubation success andpatients not subjected to interview (control group;n = 58). Extubation success was more frequent in conf-idents than in non-confidents (90 vs. 45%; p \ 0.001/positive likelihood ratio = 2.00) or in the control group(90 vs. 78%; p = 0.04). On the contrary, extubationfailure was more common in non-confidents than inconfidents (55 vs. 10%; p \ 0.001/negative likelihoodratio = 0.19). Logistic regression analysis showed thatextubation success was associated with patient’s predic-tion [odds ratio (OR) (95% CI) 9.2 (3.74–22.42) forconfidents vs. non-confidents] and with age [0.72(0.66–0.78) for age 75 vs. 65 and 1.31 (1.28–1.51) for age55 vs. 65]. It was concluded that at the end of a sustainedSBT, extubation success might be correlated with thepatients’ subjective perception of autonomous breathing.

Sedation during mechanical ventilation is commonclinical practice in the ICU and has important implica-tions for the duration of mechanical ventilation andweaning. In June Intensive Care Medicine published a

meta-analysis [34] carried out to assess the effects ofusing dexmedetomidine (D) as a sedative and analgesicagent on length of ICU stay, duration of mechanicalventilation, risk of bradycardia, and hypotension in criti-cally ill adult patients. The controls were placebo or analternative sedative agent. A total of 2,419 critically illpatients from 24 trials were subject to meta-analysis. Dwas associated with a significant reduction in length ofICU stay (weighted mean difference -0.48 days, 95% CI-0.18 to -0.78 days, p = 0.002), but not duration ofmechanical ventilation, when compared with an alterna-tive sedative agent. There was, however, significantheterogeneity in these two outcomes between the pooledstudies. D was associated with increased risk of brady-cardia requiring interventions in studies that used both aloading dose and maintenance doses greater than 0.7 lg/kg/h [relative risk (RR) 7.30, 95% CI 1.73–30.81,p = 0.007]. It was concluded that significant heteroge-neity existed between the pooled studies, and that thelimited evidence suggested that D might reduce length ofICU stay in some critically ill patients. However, the riskof bradycardia was significantly higher when both aloading dose and high maintenance doses of D were used.

Patients who require mechanical ventilation are at riskof emotional stress because of total dependence on aventilator for breathing and they know that their ability tobreathe depends on assistance from a machine. Becauseof the presence of an endotracheal tube, they cannot talkand it is extremely difficult for most of them to commu-nicate their needs. The stress may negatively impactventilator weaning and survival. Jubran et al. [35] ana-lysed whether depressive disorders in patients beingweaned from prolonged mechanical ventilation are linkedto weaning failure and decreased survival. A prospectivestudy of 478 consecutive patients transferred to a long-term acute care hospital for weaning from prolongedventilation was undertaken. A clinical psychologist con-ducted the interview with patients. Of the 478 patients,142 had persistent coma or delirium and were unable tobe evaluated for depressive disorders. Of the remaining336 patients, 142 (42%) were diagnosed with depressivedisorders. In multivariate analysis, co-morbidity score(OR 1.23, p = 0.007), functional dependence before theacute illness (OR 1.70, p = 0.03) and history of psychi-atric disorders (OR 3.04, p = 0.0001) were independentpredictors of depressive disorders. The rate of weaningfailure was higher in patients with depressive disordersthan in those without such disorders (61 vs. 33%, p =0.0001), as was mortality (24 vs. 10%, p = 0.0008). Ju-bran et al. concluded that the presence of depressivedisorders was related to factors present before the onset ofthe acute respiratory failure and that patients withdepressive disorders were more likely to experienceweaning failure and death.

Weaning from prolonged mechanical ventilation maybe also associated with mental discomfort. The same

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group of authors in another study investigated whetherpost-traumatic stress disorder (PTSD) occurs in patientsafter weaning from prolonged ventilation and determinedwhether a questionnaire administration would identifypatients at risk for developing PTSD [36]. In a prospec-tive longitudinal study, 72 patients were studied 1 weekafter weaning, and 41 patients were studied again3 months later. An experienced psychologist conducted astructured clinical interview 3 months after weaning. Toassess for the presence of PTSD-related symptoms, thepost-traumatic stress syndrome (PTSS-10) questionnairewas administered 1 week after weaning and 3 monthslater. PTSD was diagnosed in 12% of patients 3 monthsafter ventilator weaning. Patients who developed PTSDwere more likely to have a previous history of psychiatricdisorders (p \ 0.02). A PTSS-10 score higher than 20 oneweek after weaning reliably identified patients who werediagnosed with PTSD 3 months later: sensitivity 1.0;specificity 0.76; area under the receiver-operating char-acteristic curve (AUC) 0.91. It was concluded that thedevelopment of PTSD was related to the presence ofprevious mental difficulties rather than the severity of theunderlying critical illness. A PTSS-10 score higher than20 one week after weaning identified patients diagnosedwith PTSD 3 months later. This finding suggests that asimple questionnaire administered before discharge canidentify patients at risk for developing PTSD. This articlehas an accompanying editorial comment [37].

Endotracheal intubation and tracheostomy

Endotracheal intubation is one of the most commonprocedures performed in the ICU and is associated withcomplications. Jaber et al. [38] conducted an investigationto determine whether the implementation of an intubationmanagement protocol leads to the reduction of intubation-related complications in the ICU. To that end, a before–after study was done in three medical–surgical ICUs intwo university hospitals. All intubations performed duringtwo consecutive phases (6 months each) were evaluated.An initial quality control phase was followed by a phasebased on the implementation of an ICU intubationbundle management protocol. Primary endpoints werethe incidence of life-threatening complications within60 min after intubation (cardiac arrest, death, cardio-vascular collapse and hypoxaemia). The intubationprocedure in the intervention (protocol) phase (n = 121)was associated with significant decreases in both life-threatening complications (21 vs. 34%, p = 0.03) andother mild complications (9 vs. 21%, p = 0.01) com-pared with the control phase (n = 123). No differencesin other outcomes, such as ICU length of stay andmortality rates, were observed. The authors concludedthat the implementation of an intubation management

protocol can reduce immediate severe life-threateningcomplications.

Tadie et al. [39] assessed the rate of post-intubationlaryngeal injuries and extubation failure in a prospectivestudy including 136 patients extubated after more than24 h of mechanical ventilation. Fibre-optic endoscopicexamination of the larynx was systemically performedwithin 6 h after extubation in order to record four types oflaryngeal anomalies: edema, ulceration, granulation andabnormal vocal cord mobility. Laryngeal injuries occur-red in 73% of the study population and were associatedwith duration of intubation, absence of myorelaxants atintubation, emergency intubation and height/endotrachealtube size ratio. Seventeen patients were re-intubatedwithin 48 h following extubation. Laryngeal examinationof these patients more frequently showed granulation andabnormal pictures.

Many patients with respiratory failure related to neu-romuscular disease receive chronic invasive ventilationthrough a tracheostomy. Improving quality of life, ofwhich speech is an important component, is a major goalin these patients. The effects on breathing and speech of alow-level (5 cmH2O) PEEP, and of a Passy–Muirspeaking valve (PMV) during assist-control ventilationwas investigated in ten tracheotomized patients [40].During speech with PEEP, six of the ten patients had noreturn of expiratory gas to the expiratory line and,therefore, had the entire insufflated volume available forspeech, a condition met during PMV use in all patients.During speech, the respiratory rate increased by at least3 cycles/min above the backup rate in seven patients withPEEP and in none of the patients with PMV. It wasconcluded that low-level PEEP is as effective as PMV inensuring good speech quality.

Lung ultrasound

Lung ultrasound is a promising, noninvasive technique forlung and pleural pathology assessment in critically illpatients. Whole lung lavage is used to treat pulmonaryalveolar proteinosis and can be considered as a complexhuman model of controlled lung de-aeration and its pro-gressive resolution with PEEP application and diureticsadministration. Via et al. [41] described ultrasound find-ings during whole lung lavage with validated semioticsand assessed their relation to the different states of lungaeration. During one-lung ventilation and saline flooding,ultrasound findings shifted from normal/nearly normalpattern and alveolar-interstitial syndrome to alveolarconsolidation. Saline removal, re-ventilation and negativewater balance were associated with a gradual return toalveolar-interstitial syndrome, then to a normal/nearlynormal pattern. Arterial oxygenation variations were notalways consistent with lung aeration changes. These

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findings showed that lung ultrasound could reliablydescribe the different states of aeration determined by thewhole lung lavage procedure and confirmed ultrasound asan accurate technique for bedside monitoring of lungpathology.

Pleural effusions (PE) are frequent in the critically illand accurate bedside quantification of the PE volume ischallenging. Remerand [42] assessed the accuracy of amultiplane ultrasound approach to measure PE volume.The goal was to provide an accurate quantification ofsmall to large PE and to help in the clinical decisionmaking for thoracic drainage. The was study performedon 58 critically ill patients with 102 PEs and the PE wasassessed using bedside lung ultrasound. Thoracic drainagewas performed in 46 patients (59 PEs) and lung computedtomography (CT) in 24 patients (43 PEs). Ultrasound PEvolume was compared with either the volume of thedrained PE or PE volume assessed on lung CT. Ultra-sound PE volume was correlated with drained PE volume(r = 0.84, p \ 0.001) and with CT PE volume (r = 0.90,p \ 0.001). Mean biases between ultrasound and actualvolumes of PE were -33 ml when compared withdrainage (limits of agreement -292 to ?227 ml) and-53 ml when compared with CT (limits of agreement-303 to ?198 ml). It was concluded that the multiplaneapproach increases the accuracy of lung ultrasound tomeasure the volume of large to small PEs and thatthis method can be recommended for the assessment ofthese PE.

Paediatrics

Respiratory

Whilst the focus of much research into the mechanisms oflung injury focus on the adult lung, we are reminded byboth Sapru and Tissieres that lung injury occurs at all ages[43, 44]. Sapru studied the relationship between increasedplasma and pulmonary oedema fluid levels of plasmino-gen-activator inhibitor-1 (PAF-1), an anti-fibrinolyticagent which is activated during inflammation, and out-come of ALI in children. They demonstrated that as inadults, higher PAF-1 levels are associated with increasedmortality and fewer ventilator-free days in children withALI, suggesting that PAF-1 may serve as a useful bio-marker of prognosis in children with ALI. Tissieresstudied the effect of prophylactic surfactant on pulmonaryoutcomes in a group of very low birthweight infants.Previously, early lung recruitment (ELR) and high fre-quency oscillatory ventilation (HFOV) in combinationwith prophylactic surfactant were reported to reducemortality and improve pulmonary outcomes. In this study,surfactant was only administered to those babies withunsatisfactory response to ELR. The rationale behind this

approach is that (1) an easily recruitable lung in the earlystage of RDS may not need exogenous surfactant treat-ment for sufficient lung opening and (2) gentle ventilationin an ‘‘open lung’’ may preserve surfactant function byavoiding a major inflammatory stimulus within the lungs,as suggested by experimental data. The authors showedthat implementation of an ELR strategy with HFOV andselective surfactant administration resulted in no dis-cernable detrimental effect on respiratory outcomes andmortality in VLBW infants presenting with RDS, raisingthe question of whether current practice of universalsurfactant administration should be reconsidered. Ulti-mately, when considering the management of very severerespiratory failure in term neonates, ECMO has a well-established place. The report by Schaible [45] describesthe outcomes of neonatal respiratory ECMO from a largeEuropean centre. Overall survival rates of 67% breakdown to 94% in babies with meconium aspiration and62% in those with congenital diaphragmatic hernia. Thereport showed a clear association between early referraland higher rate of survival (77% survival for babiesreferred in the first 24 h of life compared with 54% forthose referred at greater than 24 h of age).

Whilst much research focuses on biochemical andcellular mechanisms of lung injury and repair, importantstudies continue to emphasise to clinicians the importanceof understanding lung physiology and the interactions ofthe lung with respiratory support systems. For example,Tingay et al. [46] described the impact of differentendotracheal suction techniques on regional end-expira-tory lung volume (EELV) and tidal volume in asurfactant-deficient piglet model. Closed suction (CS)methods and the use of smaller suction catheters havebeen claimed to result in less loss of recruitment duringtracheal suction in neonates. Tingay compared opensuction (OS) with two closed techniques when usingeither 5- or 8-French-gauge suction catheters. Theirresults question this, as recovery of lung volume andventilation after endotracheal tube (ETT) suction wasrapid and uniform throughout the lung with all suctiontechniques. Despite the 10- to 14-fold greater loss ofEELV seen during OS, and CS with an 8-FG cathetercompared with 5-FG CS, the regional EELV and VT 10 safter suction did not differ. This rapid recovery is con-sistent with studies comparing global DEELV during andafter suction using open and closed methods and suggeststhat carefully conducted open suction remains a safe andeffective option. Carlisle et al. [47] from the sameresearch group also took a step back to basic physiologyin exploring the influence of gravity on the distribution ofventilation and perfusion within the neonatal chest.Whereas it is widely recognised that the diseased adultlung is particularly prone to ventilation–perfusion mis-matching, even when ventilation has been optimised,little is known about lung perfusion and the distributionof blood volume within the preterm lung. Traditional

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methods of determining lung perfusion, such as radionuclidescans, are not feasible in the ventilated neonate; however, thedevelopment of electrical impedance tomography (EIT) as anoninvasive, real-time, radiation-free method of measuringthe relative change in impedances within regions of a crosssection of the thorax facilitates the study of changes in gas,tissue and blood volumes. Air generates a greater impedancechange than blood, and EIT has been used to measureregional ventilation in newborn infants with recent techno-logical advances now enabling isolation of the EIT signalwithin the cardiac frequency domain thus allowing deter-mination of cyclical changes in blood volume. Carlisle et al.demonstrated elegantly that gravity does indeed influenceventilation–perfusion relationships in the lungs of preterminfants, a finding which provides evidence to support clinicalpractice and future research including the use of positioningtechniques and ventilatory strategies in the management ofpreterm lung disease.

In recent years, continuous positive airway pressurethrough nasal cannulae (nCPAP) provided to preterm neo-nates with respiratory failure has been shown to be effectivein stabilizing proximal airways and surfactant-deficientalveoli, improving oxygenation, and to reduce the need forintubation. Infants who fail nCPAP may theoretically benefitfrom a noninvasive rescue ventilation. In a laboratory benchexperiment, De Luca et al. [48] described the effect of nasalcannulae of varying diameter on the delivery of ventilation toa model lung using a widely used HFO ventilator. Theauthors concluded in this preliminary study that nasal prongdiameter and flow are the main determinants of the deliveredtidal volume and total ventilation. A great deal of additionalbench and animal work will be required to further explorethis potential extension to the noninvasive ventilatoryarmamentarium.

The outbreak of influenza A (H1N1) in the southernhemisphere during the summer of 2009 heralded similarsurges of H1N1 infection in the northern winter of2009–2010. Farias et al. [49] reported on the managementand outcomes of 147 children admitted to paediatric inten-sive care units (PICUs) in Argentina during that period withH1N1 infection. Of those children, 94% were invasivelyventilated, with a reported mortality of 39%. Of the childrenwho died, whilst 59% suffered from a chronic medicalcondition, 41% were apparently previously healthy. Thisreport is consistent with others in showing that the mortalityrate from H1N1 influenza A is higher than that usuallyrecorded for seasonal influenza A, and brings into focus thedeaths of not only ‘at risk’ children, but those with no pre-vious health concerns. Immunisation programmes need totake careful account of such reports.

Sepsis and multiorgan failure

Abdominal compartment syndrome (ACS), defined as asustained intra-abdominal pressure (IAP) of greater than

20 mmHg, is of concern because it is associated withmultiorgan system failure and has a high mortality rate.Patient position and body mass index (BMI) affect intra-abdominal pressure in adults and Ejike et al. [50] exploredfactors influencing IAP in 77 mechanically ventilatedchildren less than 18 years of age. Paired measurementsof IAP were measured in supine and 30� head-up posi-tions every 6 h over a 24-h period. Mean IAP was10.6 ± 4.0 mmHg at 30� head up, and 8.4 ± 4.0 mmHgin the supine position. No correlation was found betweenIAP and BMI or BMI percentiles. The authors concludedthat whilst body position should be taken into accountwhen interpreting IAP, BMI did not seem to influenceIAP in their population of children and young people.

Peroxisome proliferator-activated receptor-c (PPARc)is a ligand-binding nuclear receptor whose activationinfluences the inflammatory response. The mechanism ofcytokine inhibition in activated monocytes/macrophagesoccurs, in part, through repression of several inflamma-tory response genes, including activator protein-1 andnuclear factor-jB (NF-jB). The endogenous activator ofPPARc, 15d-PGJ2, exerts beneficial anti-inflammatoryeffects, in part, through inhibition of NF-jB activationand it is known that sepsis-induced reduction in PPARcexpression is reversed by in vivo treatment with PPARcligands. In a single-centre, prospective case–control studyin critically ill children with systemic inflammatoryresponse syndrome, sepsis or septic shock Kaplan et al.[51] determined that PPARc nuclear protein expressionwas decreased but PPARc activity was increased inperipheral blood monocytes from children with septicshock compared with controls. In addition, Kaplaninvestigated the effects of sepsis on 15d-PGJ2 and thedownstream targets of PPARc activity, high-molecular-weight adiponectin (HMWA) and resistin [51]. Theirresults show that PPARc activity on day 1 was signifi-cantly higher in patients with higher paediatric risk ofmortality (PRISM) score compared with controls. Patientswith resolved sepsis had increased levels of 15d-PGJ2

compared with patients with systemic inflammatoryresponse syndrome (SIRS) and septic shock. In summarythese findings suggest that sepsis is associated withaltered PPARc expression and activity in monocytes.Further studies are needed to understand the mechanismsunderlying changes in PPARc and their downstream tar-gets in sepsis, as potential biomarkers or to informtherapeutic strategies. Sarafidis et al. [52] reported on theuse of a potential biomarker, specifically serum solubletriggering receptor expressed on myeloid cells TREM-1,in the context of the early diagnosis of late-onset sepsis inneonates. S-TREM-1 and IL6 were measured when signsof sepsis were evident. Receiver operating curve (ROC)analysis for s-TREM-1 (AUC 0.733, p = 0.005) com-pared favourably with IL-6 (AUC 0.892, p = 0.001) foridentification of infected neonates. There was, however,no statistically significant difference between the two

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biomarkers, and their deployment when sepsis wasalready suspected brings into question the general use-fulness of the markers, given that clinical suspicion hadalready been aroused.

Agbeko et al. [53] sought to determine if commonpolymorphisms in the endotoxin recognition complexinfluenced the acute phase response as determined by thedevelopment of SIRS and platelet count on admission ofchildren to critical care in a prospective observationalcohort study. Paediatric intensive care patients (n = 913)were genotyped for common functional polymorphisms inthe endotoxin recognition complex, including Toll-likereceptor 4 (TLR4). TLR4 variant alleles were found to beassociated with lower platelet counts across a range ofages and precipitating insults but that they do not influ-ence the incidence of SIRS. This finding may reflectredundancy and ‘robustness’ in the pathways leading toSIRS or the lack of specificity of this endpoint. Plateletcount may vary with TLR4 genotype because it may besufficiently sensitive and more linearly related toinflammation than other markers or, alternatively, theremay be a direct TLR4-mediated platelet effect.

Two papers in the paediatric pages of Intensive CareMedicine reported new approaches to the characterisationand management of acute adrenal insufficiency in PICU.Dupuis et al. [54] reported a study in which serial bloodcortisol and adrenocorticotropic hormone (ACTH) levelswere measured in a series of 28 children with traumaticbrain injury (TBI). Secondary adrenal insufficiency wasdefined as cortisol below 200 nmol/l with ACTH below12 pmol/l. Secondary adrenal insufficiency was detectedin 10 (37%) of children and was associated with a rangeof adverse clinical endpoints, raising the importantquestion of whether cortisol replacement is needed insuch TBI patients. A word of caution on measurement andinterpretation of cortisol levels in critical illness is raisedby Zimmerman [55] who points out that whilst histori-cally adrenal function has been assessed by measuringtotal cortisol (TC) there is an evolving consensus thatbecause free cortisol (FC) rather than protein-boundcortisol is responsible for the biochemical actions of thishormone the FC fraction should be measured as ‘func-tionally important’. This is of particular relevance incritical illness as levels of cortisol-binding globulin andother proteins which bind cortisol such as albumin arealtered. One practical drawback, however, is that thetraditional assay method used to determine plasma-freecortisol, equilibrium dialysis, required large blood vol-umes and prolonged fractionation time precedinganalysis. Zimmerman reported a pilot study on the mea-surement of FC using a chemiluminescence assay,determining that FC could be measured both accuratelyand rapidly (analyser time 38 min) using the new assaymethod which requires only 0.4 ml blood. Utilization ofthe new method for free FC analysis will require confir-mation utilizing larger cohorts of both healthy and

critically ill children but suggests that real-time FCquantification may be available to help guide clinicaldecision making regarding cortisol replacement therapyfor children with critical illness.

Views on the usefulness of ECMO in shock are mixed.It is logical to suppose that in situations where cardiacdysfunction predominates as is the case in acute fulminantmyocarditis, veno-arterial ECMO can be expected tosupport patients effectively. Enterovirus 71 (EV71) isusually a minor childhood illness, but can occasionallylead to cardiovascular collapse with acute cardiacinvolvement and cardiogenic shock. Jan and colleagues[56] reported a series of 13 cases of ECMO support inchildren with severe EV71 infection of whom 10 weresuccessfully weaned from ECMO and survived. Themedian duration of ECMO support was 93 ± 33 h.Determining which patients to support with ECMO can bechallenging, but in sepsis, focussing on cases with pre-dominant cardiac involvement is recommended.

Neurological critical care

Head trauma is an important factor contributing tochildhood morbidity and mortality. Injury is suffered intwo distinct phases. The primary injury occurs at themoment of impact and results from mechanical forces thatcause direct disruption of the brain parenchyma. Thesecond phase of injury is a sequelae of events triggered bythe primary injury and includes endogenous factors suchas metabolic, cellular and biochemical derangements andexogenous factors such as hypoxia and hypotension. Overthe last two decades, several studies have evaluatedvasospasm in adult head trauma patients although thepaediatric literature is extremely sparse. O’Brien [57]reported the results of a prospective observational studyof 22 children with moderate or severe traumatic braininjury. Transcranial Doppler ultrasound examinationswere performed to detect and follow vasospasm. Of thechildren examined, 45.5% developed vasospasm in themiddle cerebral artery, and 18.2% in the basilar arterywith onset typically on day 2–3. The authors concludedthat vasospasm, however, be an unrecognized phenome-non contributing to secondary brain injury in paediatrichead trauma patients.

It has long been assumed that age and brain maturityhave important influences on cerebral perfusion pressure(CPP) and autoregulation. Walter et al. [58] reported anexperimental approach, in which a gradual reduction inCCP was induced, to estimate the threshold levels ofincreased glutamatergic and dopaminergic transmitterrelease responsible for excitotoxicity in newborn andjuvenile pigs (i.e. the functional lower limit of cerebralautoregulation). The resulting effects on CBF and brainoxidative metabolism were quantified, and striatal

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glutamate and dopamine release were monitored bymicrodialysis. The authors showed an age-dependentthreshold difference for significant extracellular glutamateand dopamine release following a gradual decrease inCPP. Juvenile pigs showed a marked elevation in thelevels of both transmitters as early as at a moderatereduction of CPP, whereas this response was not apparentin newborn piglets which may suggest that the immaturebrain is less susceptible to damage through excitotoxicmechanisms than the more mature brain.

Hypoxia–ischaemia (HI) is a major cause of foetalbrain damage and is effectively untreatable except in asupportive paradigm. Fathali et al. [59] provided anintriguing insight into a potential new therapeutic avenuefor such babies in an investigation of the effect of gran-ulocyte-colony stimulating factor (GCSF) on HI-inducedbrain damage in infant rats, following a 2-h period ofcarotid ligation accompanied by hypoxia (8% oxygen).Compared with control animals, GCSF administered dailyfor 5 or 10 days following HI appeared to afford long-term neuroprotection assessed against both morphologicaland functional criteria. This interesting finding deservesfurther exploration in a clinical setting.

Parents are often frustrated at the inability of cliniciansto accurately predict outcomes in paediatric neurointen-sive care. Carrai et al. [60] published a review of theliterature on the use of somato-sensory evoked potentials(SEPs) in comatose children. The authors selected 14studies covering 732 patients. In individual papers, thepresence of SEP predicted favourable outcomes as shownby the area under both sROC curves being 0.958. Thesame value was shown by SEP absence for predictingunfavourable outcomes. All covariates showed no sig-nificant effects on diagnostic accuracy, but only a slightnon-significant trend. For SEP grading, a simple subgroupanalysis showed a high positive predictive value (PPV)for non-awakening for absence of SEPs (PPV 97.0%) anda high prognostic power to predict awakening for normalSEPs (PPV 92.2%). Pathological SEPs did not showreliable predictivity. In children, the presence of SEPsshowed a high prognostic power similar to that in adults.The study supports the use of SEPs in the integratedprocess of outcome prediction after acute brain injury inchildren. Caution is recommended in predicting unfa-vourable outcomes in patients with an absence of SEPs inboth TBI and hypoxic-ischaemic encephalopathy (HIE)comas. The authors suggest that future studies are neededto resolve the issue of the effect of etiology and age onSEP’s predictive power. This report is, however, animportant snapshot of the current state of knowledge onthe use of SEPs in paediatric coma.

The ‘science’ of improving outcome through betterorganisation or delivery of care is having a great impact incritical care units across the globe. For example theimplementation of well-designed ‘care bundles’ aimed atfor instance reducing nosocomial infection rates have

been shown to be both clinically and economicallyeffective. Decisions on where care is delivered and how itis delivered are important but must be informed by gooddata describing the population, the intervention or treat-ment and outcomes. Cogo et al. [61] investigated theoutcomes from the care received by 1,265 Italian childrenadmitted to adult intensive care units between 2003 and2007 using data obtained from the ‘Project Margherita’quality assessment and improvement database comparingthese to a cohort of PICU children from 1994 to 1995.Using PRISM for risk adjustment, Cogo et al. found thatthe standardised mortality ratio was slightly worse foradult ICU care [1.11 (95% CI 0.91–1.31)] than for PICUcare [1.04 (95% CI 0.88–1.19)]. The most importantmessage from this paper is not, however, that promul-gated by the author, i.e. that PICU care is best, but israther that to measure performance in a healthcare system,prospective, relevant data are needed. Just as in clinicalresearch, when measuring quality, safety, outcomes ormanaging cost, data is king.

Straney et al. [62] developed models to determine theefficiency of PICUs contributing data to the Australianand New Zealand Paediatric Intensive Care (ANZPIC)Registry which collects data from all of the nine specialistPICUs in Australia and New Zealand. Length of stay(LoS) has been cited widely as a suitable marker forquantifying resource usage. However, efforts to compareLoS have been hampered by the difficulty in calibrating tocase mix within centres and other local organisationalfactors. A method for quantifying variation of mean risk-adjusted LoS among PICUs was recently reported byRapoport et al. [63]. The Rapoport–Teres graph plotsresource usage against clinical performance. It provides asimple and intuitive method for comparing efficiencyamong units and provides a visual representation of cost-effectiveness. Using this technique, the authors demon-strated apparent differences in efficiency among PICUswhich may be important for healthcare providers (PICUs)or healthcare commissioners to understand.

When assessing outcome for operational or researchreasons, mortality is of only limited use in paediatricintensive care as the rate of mortality is now low andtherefore use of death as an endpoint necessitates largesample sizes. The paediatric logistic organ dysfunction(PELOD) score was therefore developed as an outcomemeasure for clinical trials in the paediatric intensive careunit [64]. In the PELOD score markers of organ dys-function are graded according to severity of derangementand assigned a score which is then summed in a com-posite score. The PELOD score has been validated inseveral populations in Europe and Canada, but Garciaet al. [65] recognised the importance of road-testing thePELOD score as widely as possible. They determined thatthe score performed well in discriminating between goodand bad outcomes in children in their two Brazilian PI-CUs, although the score was poorly calibrated in their

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population (calibration of the score = accuracy ofobserved vs. predicted outcomes). This paper, indepen-dent of the authors of the score, provides a useful insightinto the undoubted strengths and some potential weak-nesses of what they nevertheless conclude to be a usefuladditional PICU scoring tool.

Peeters et al. [66] prospectively examined the risk-adjusted mortality of children admitted to a large Dutchintensive care PICU to determine whether ‘out-of-hours’admission was associated with poorer outcomes than ‘in-hours’ admission, given that the senior intensivists werenot resident in the hospital out-of-hours. Of the 3,212admissions studied, 66% occurred in-hours. No differencein standardised mortality rate was established between in-and out-of-hours admissions in this single unit. Thisreport adds to the literature which remains confusing withsome of the few reports on this topic suggesting that hourof admission or the immediate presence of the most seniorintensivist makes no difference, whilst others suggest thatsenior cover improves outcomes.

A strategy widely promoted over recent years in bothadult and paediatric critical care is the use of ‘alert’ or‘early-warning’ scores to detect deteriorating patients innon-ICU areas. Chapman et al. [67] systematicallyreviewed studies reporting paediatric alert criteria withassessment of their validity, reliability, clinical effec-tiveness and clinical utility. Eleven studies were includedand described ten alert criteria. Only three of the fivestudies which published the predictive value of paediatricalert criteria reported appropriate methodology. Only onestudy evaluated reliability and no study addressed theclinical utility of paediatric alert criteria. The authorstherefore had no difficulty in concluding that the evidencesupporting the use of clinical use of paediatric alert cri-teria is weak and that prospective development andevaluation are needed before their widespread adoptioninto clinical practice.

Naghib et al. [68] reported the outcomes of childrenstaying more than 28 days in a Dutch PICU. During thestudy period 2,607 patients were admitted on 3,700occasions for a total of 16,013 admission days. Of thisgroup 4.4% (116/2,607) of patients were identified as verylong-stay patients, consuming 63% (10,055/16,013) ofPICU admission days. Mortality in this group was 5 timeshigher (22%) than that for the whole PICU population(4.6%). The investigators reported that withdrawal orlimitation of care preceded 70% of deaths. This studyemphasises the large burden that prolonged intensive caredependency places on the child, their family and thehealthcare system. There is a clear need to adopt strate-gies which promote rapid recovery and therefore reducethe need for long-term critical care status, but also a needto provide realistic options for limitation of critical care ifafter careful assessment and discussion children are nolonger benefiting from intensive support.

CPR

The development of the scientific basis of cardiopulmo-nary resuscitation continues to evolve. Iglesias et al. [69]conducted a comparison of tidal volumes achieved withventilation plus compressions (VC) versus chest com-pressions alone (CC) in 12 infant piglets after inducedhypoxic cardiac arrest. VC achieved a similar tidal vol-ume to calculated requirements, whereas tidal volumewith CC was very low. The VC technique achieved ahigher pH and PO2 and a lower PCO2 than CC. Theclinical relevance of these findings to clinical practiceremains to be established, although there is some evi-dence that in the early stages of CPR effective CC alonemay lead to better perfusion of vital organs.

Adrenaline is the recommended drug for the treatmentof cardiac arrest (CA) both in children and adults basedon its vasoconstrictive and inotropic effects. Vasopressinand terlipressin, a synthetic vasopressin analogue with alonger half-life, produce vasoconstriction by the stimu-lation of V1 receptors. Several studies have shown thatvasopressin increases vital organ blood flow and cerebraloxygen delivery; in addition, adrenaline plus vasopressinachieved a higher return of spontaneous circulation(ROSC) and neurological recovery when compared withadrenaline alone in adult animals with CA secondary toventricular fibrillation (VF). Initial clinical studies withvasopressin plus adrenaline were not found to improve theresults in adult patients with ventricular fibrillation andpulseless electrical activity compared with adrenalinealone, but there was an improvement in the results ofresuscitation in cases of asystole and refractory CA. Lo-pez-Herce [70] compared terlipressin with adrenaline inan animal model of paediatric asphyxial cardiac arrest.They determined only a non-significant trend towardsbetter outcome when terlipressin was combined withadrenaline compared with either drug alone. Furtherevaluations of the role of vasopressin analogues in pae-diatric CPR are needed.

Drug treatment

Drug handling is notoriously difficult to predict in thepaediatric critical care environment, as organ functiondeteriorates, extracorporeal technologies are deployed orcritical interactions occur between drugs. Wildschut et al.[71] described a simple study in which a range of com-mon PICU drugs including sedative, analgesics andantibiotics were added to a range of recirculating neonataland paediatric ECMO circuits. Unsurprisingly, lipophilicdrugs such as fentanyl were most likely to be highlyabsorbed by the ECMO circuit components, althoughsome types of ECMO circuit bind less fentanyl than

406

others. Morphine is less lipophilic and may therefore bethe opioid of choice during ECMO. Another issue withdrug delivery was highlighted by Jack et al. [72] whoshowed in a an elegant animal study that particulatecontamination of infusion solutions can lead to biolog-ical derangements. The authors confirmed the existenceof particulate contamination in infusions despite astringent infusion regime. In vitro investigation of anumber of inflammatory mediators demonstrated thatparticulate contaminants had the effect of suppressingmacrophage and endothelial cytokine secretion. Theimportance of reducing particulate contamination toprevent immune modulation is recommended by theauthors.

Two sedation studies in PICU populations were pub-lished in Intensive Care Medicine in 2010. Dailyinterruption of analgeso-sedatives has been recommendedas a component of optimal care in adult critical carefollowing the landmark paper from Kress et al. [73].Wildschut et al. [74] reported on the feasibility of anal-gesia and sedation interruption in 20 neonates on ECMO.The prospective study was undertaken in a single PICU.Midazolam and morphine were discontinued after ECMOcannulations were completed and only restarted based onCOMFORT-B and visual analogue pain nurse-observedscores. Time without morphine before restart was 10.25 h(IQR 5–24.1) and time without midazolam was 16.5 h(IQR 6.6–29.6). No accidental extubations, decannula-tions or bleeding occurred in patients undergoing sedationinterruption. This study emphasises the surprisingly slowmetabolism of analgo-sedative drugs in the sick neonateand should encourage the adoption of endpoint-relateddrug administration wherever possible, especially incritically ill neonates with organ dysfunction of criticalillness potentially compounding organ immaturity.Chrysostomou et al. [75] reported a prospective obser-vational study of the use of dexmedetomidine in 51children in PICU with congenital heart disease (CHD).Dexmedetomidine is a highly selective alpha 2-agonistwith sedative and analgesic properties that has beenshown to reduce the postoperative requirements of addi-tional intravenous sedative and analgesic agents.Dexmedetomidine mediates its effects through a complexmechanism that involves both presynaptic and postsyn-aptic receptor activation. Activation of the presynapticalpha-2 adrenoreceptors on sympathetic nerves and thecentral nervous system induces sympatholysis, which isresponsible for the hypotensive and bradycardic sideeffects. Although dexmedetomidine appears to have awide safety margin, there have been concerns related tothe development of sudden sinus node pauses, symp-tomatic bradycardia and its potential to cause atrio-

ventricular nodal block and prolongation of the QTcinterval. This study characterised the electrocardiographic(ECG) effects of dexmedetomidine in children with CHDand children undergoing cardiothoracic surgery. Theprinciple findings of this detailed electrophysiologicalstudy showed that in the dexmedetomidine group, heartrate (HR) decreased from 140 ± 22 to 115 ± 23. Whencompared with the control group, none of the ECGintervals showed any difference other than a trendtowards lower HR (p = 0.08). The use of dexmedetomi-dine in patients with CHD was not associated with anyclinically significant ECG abnormalities.

Endocrine and metabolic

Plumpton et al. [76] characterised the thyroid hormoneand cortisol concentrations in a prospective observationalstudy of 52 infants younger than 3 months of age aftercongenital heart surgery. In brief, in this well-presentedand data-rich study, infants with low triiodothyronine(B3.7 pmol/l) or high cortisol concentration on postop-erative admission to the PICU were more likely to have ahigh inotrope requirement on postoperative day 2(p = 0.003 and p = 0.0006, respectively) or needmechanical ventilation for longer than 96 h (p = 0.04and p = 0.002, respectively). Total cortisol concentrationless than 200 nmol/l was found in 16 (31%) infants. Freecortisol levels were found to follow total cortisol levelsclosely in this study. There was no association betweenlow cortisol and postoperative complications. The authorsspeculate on the relevance of these derangements inendocrine function and the potential to intervene withsupplements to ‘correct’ the abnormalities [76].

Kyle et al. [77] presented a look-back report of theassociation between organ dysfunction and hyper-glycaemia in 110 critically ill children. Organdysfunction (C3 versus \3 organs) was significantlyassociated with hyperglycaemia for at least 24 h andhypoglycaemia. There was a trend towards increasedmortality in the hyperglycaemic group. These findingsare not surprising given the reports from many otherICU populations of similar associations. Whether apolicy of permissive or tight glycaemic control shouldbe deployed in the management of critically ill adults isnot yet settled [78], and in the paediatric ICU there isonly one published randomised controlled trial which issupportive of tight glycaemic control [79]. The resultsof the CHiP trial, a multicentre trial of tight glycaemiccontrol versus ‘usual’ care, will complete recruitment inlate 2011 [80].

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