Iatrogenic cerebral amyloid angiopathy in older adults.

BACKGROUND AND PURPOSE: An increasing number of cases of iatrogenic cerebral amyloid angiopathy (CAA) have now been reported worldwide. Proposed diagnostic criteria require a history of medical intervention with potential for amyloid-ß transmission, for example those using cadaveric dura mater or requiring instrumentation of the brain or spinal cord. Clinical presentation occurs after an appropriate latency (usually three or four decades); to date, most patients with iatrogenic CAA have had 'early-onset' disease (compared to sporadic, age-related, CAA), as a consequence of childhood procedures. RESULTS: We describe five cases of possible iatrogenic CAA in adults presenting in later life (aged 65 years and older); all had prior neurosurgical interventions and presented after a latency suggestive of iatrogenic disease (range 30-39 years). Use of cadaveric dura mater was confirmed in one case, and highly likely in the remainder. CONCLUSION: The presentation of iatrogenic CAA in older adults widens the known potential spectrum of this disease and highlights the difficulties of making the diagnosis in this age group, and particularly in differentiating iatrogenic from sporadic CAA. Increased vigilance for cases presenting at an older age is essential for furthering our understanding of the clinical phenotype and broader implications of iatrogenic CAA.

Clinical considerations in early-onset cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is an important cerebral small vessel disease associated with brain haemorrhage and cognitive change. The commonest form, sporadic amyloid-ß CAA, usually affects people in mid- to later life. However, early-onset forms, though uncommon, are increasingly recognized and may result from genetic or iatrogenic causes that warrant specific and focused investigation and management. In this review, we firstly describe the causes of early-onset CAA, including monogenic causes of amyloid-ß CAA (APP missense mutations and copy number variants; mutations of PSEN1 and PSEN2) and non-amyloid-ß CAA (associated with ITM2B, CST3, GSN, PRNP and TTR mutations), and other unusual sporadic and acquired causes including the newly-recognized iatrogenic subtype. We then provide a structured approach for investigating early-onset CAA, and highlight important management considerations. Improving awareness of these unusual forms of CAA amongst healthcare professionals is essential for facilitating their prompt diagnosis, and an understanding of their underlying pathophysiology may have implications for more common, late-onset, forms of the disease.

Iatrogenic cerebral amyloid angiopathy: an emerging clinical phenomenon.

In the last 6 years, following the first pathological description of presumed amyloid-beta (Aß) transmission in humans (in 2015) and subsequent experimental confirmation (in 2018), clinical cases of iatrogenic cerebral amyloid angiopathy (CAA)-attributed to the transmission of Aß seeds-have been increasingly recognised and reported. This newly described form of CAA is associated with early disease onset (typically in the third to fifth decade), and often presents with intracerebral haemorrhage, but also seizures and cognitive impairment. Although assumed to be rare, it is important that clinicians remain vigilant for potential cases, particularly as the optimal management, prognosis, true incidence and public health implications remain unknown. This review summarises our current understanding of the clinical spectrum of iatrogenic CAA and provides a diagnostic framework for clinicians. We provide clinical details for three patients with pathological evidence of iatrogenic CAA and present a summary of the published cases to date (n=20), identified following a systematic review. Our aims are: (1) To describe the clinical features of iatrogenic CAA, highlighting important similarities and differences between iatrogenic and sporadic CAA; and (2) To discuss potential approaches for investigation and diagnosis, including suggested diagnostic criteria for iatrogenic CAA.

Small Vessel Disease and Ischemic Stroke Risk During Anticoagulation for Atrial Fibrillation After Cerebral Ischemia.

BACKGROUND AND PURPOSE: The causes of recurrent ischemic stroke despite anticoagulation for atrial fibrillation are uncertain but might include small vessel occlusion. We investigated whether magnetic resonance imaging markers of cerebral small vessel disease (SVD) are associated with ischemic stroke risk during follow-up in patients anticoagulated for atrial fibrillation after recent ischemic stroke or transient ischemic attack. METHODS: We analyzed data from a prospective multicenter inception cohort study of ischemic stroke or transient ischemic attack anticoagulated for atrial fibrillation (CROMIS-2 [Clinical Relevance of Microbleeds in Stroke Study]). We rated markers of SVD on baseline brain magnetic resonance imaging: basal ganglia perivascular spaces (number ≥11); cerebral microbleeds (number ≥1); lacunes (number ≥1); and white matter hyperintensities (periventricular Fazekas grade 3 or deep white matter Fazekas grade ≥2). We investigated the associations of SVD presence (defined as presence of ≥1 SVD marker) and severity (composite SVD score) with the risk of ischemic stroke during follow-up using a Cox proportional hazards model adjusted for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65-74, female score. RESULTS: We included 1419 patients (mean age: 75.8 years [SD, 10.4]; 42.1% female). The ischemic stroke rate during follow-up in patients with any SVD was 2.20 per 100-patient years (95% CI, 1.60-3.02), compared with 0.98 per 100 patient-years (95% CI, 0.59-1.62) in those without SVD (P=0.008). After adjusting for congestive heart failure, hypertension, age >75, diabetes, stroke, vascular disease, age 65-74, female score, SVD presence remained significantly associated with ischemic stroke during follow-up (hazard ratio, 1.89 [95% CI, 1.01-3.53]; P=0.046); the risk of recurrent ischemic stroke increased with SVD score (hazard ratio per point increase, 1.33 [95% CI, 1.04-1.70]; P=0.023). CONCLUSIONS: In patients anticoagulated for atrial fibrillation after ischemic stroke or transient ischemic attack, magnetic resonance imaging markers of SVD are associated with an increased risk of ischemic stroke during follow-up; improved stroke prevention treatments are required in this population. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02513316.

Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants.

OBJECTIVE: We investigated the contribution of small vessel disease (SVD) to anticoagulant-associated intracerebral haemorrhage (ICH). METHODS: Clinical Relevance of Microbleeds in Stroke-2 comprised two independent multicentre observation studies: first, a cross-sectional study of patients with ICH; and second, a prospective study of patients taking anticoagulants for atrial fibrillation (AF) after cerebral ischaemia. In patients with ICH, we compared SVD markers on CT and MRI according to prior anticoagulant therapy. In patients with AF and cerebral ischaemia treated with anticoagulants, we compared the rates of ICH and ischaemic stroke according to SVD burden score during 2 years follow-up. RESULTS: We included 1030 patients with ICH (421 on anticoagulants), and 1447 patients with AF and cerebral ischaemia. Medium-to-high severity SVD was more prevalent in patients with anticoagulant-associated ICH (CT 56.1%, MRI 78.7%) than in those without prior anticoagulant therapy (CT 43.5%, p<0.001; MRI 64.5%, p=0.072). Leukoaraiosis and atrophy were more frequent and severe in ICH associated with prior anticoagulation. In the cerebral ischaemia cohort (779 with SVD), during 3366 patient-years of follow-up the rate of ICH was 0.56%/year (IQR 0.27-1.03) in patients with SVD, and 0.06%/year (IQR 0.00-0.35) in those without (p=0.001); ICH was independently associated with severity of SVD (HR 5.0, 95% CI 1.9 to 12.2,p=0.001), and was predicted by models including SVD (c-index 0.75, 95% CI 0.63 to 0.85). CONCLUSIONS: Medium-to-high severity SVD is associated with ICH occurring on anticoagulants, and independently predicts ICH in patients with AF taking anticoagulants; its absence identifies patients at low risk of ICH. Findings from these two complementary studies suggest that SVD is a contributory factor in ICH in patients taking anticoagulants and suggest that anticoagulation alone should no longer be regarded as a sufficient 'cause' of ICH. TRIAL REGISTRATION: NCT02513316.

Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura.

Amyloid-ß transmission has been described in patients both with and without iatrogenic Creutzfeldt-Jakob disease; however, there is little information regarding the clinical impact of this acquired amyloid-ß pathology during life. Here, for the first time, we describe in detail the clinical and neuroimaging findings in 3 patients with early onset symptomatic amyloid-ß cerebral amyloid angiopathy following childhood exposure to cadaveric dura (by neurosurgical grafting in 2 patients and tumor embolization in a third). Our observations provide further in vivo evidence that cerebral amyloid angiopathy might be caused by transmission of amyloid-ß seeds (prions) present in cadaveric dura and have diagnostic relevance for younger patients presenting with suspected cerebral amyloid angiopathy. Ann Neurol 2019; 1-7 ANN NEUROL 2019;85:284-290.

Longer term stroke risk in intracerebral haemorrhage survivors.

OBJECTIVE: To evaluate the influence of intracerebral haemorrhage (ICH) location on stroke outcomes. METHODS: We included patients recruited to a UK hospital-based, multicentre observational study of adults with imaging confirmed spontaneous ICH. The outcomes of interest were occurrence of a cerebral ischaemic event (either stroke or transient ischaemic attack) or a further ICH following study entry. Haematoma location was classified as lobar or non-lobar. RESULTS: All 1094 patients recruited to the CROMIS-2 (Clinical Relevance of Microbleeds in Stroke) ICH study were included (mean age 73.3 years; 57.4% male). There were 45 recurrent ICH events (absolute event rate (AER) 1.88 per 100 patient-years); 35 in patients presenting with lobar ICH (n=447, AER 3.77 per 100 patient-years); and 9 in patients presenting with non-lobar ICH (n=580, AER 0.69 per 100 patient-years). Multivariable Cox regression found that lobar ICH was associated with ICH recurrence (HR 8.96, 95% CI 3.36 to 23.87, p<0.0001); similar results were found in multivariable completing risk analyses. There were 70 cerebral ischaemic events (AER 2.93 per 100 patient-years); 29 in patients presenting with lobar ICH (AER 3.12 per 100 patient-years); and 39 in patients with non-lobar ICH (AER 2.97 per 100 patient-years). Multivariable Cox regression found no association with ICH location (HR 1.13, 95% CI 0.66 to 1.92, p = 0.659). Similar results were seen in completing risk analyses. CONCLUSIONS: In ICH survivors, lobar ICH location was associated with a higher risk of recurrent ICH events than non-lobar ICH; ICH location did not influence risk of subsequent ischaemic events. TRIAL REGISTRATION NUMBER: NCT02513316.

Statins and the risk of intracerebral haemorrhage in patients with stroke: systematic review and meta-analysis.

OBJECTIVE: Whether statins increase the risk of intracerebral haemorrhage (ICH) in patients with a previous stroke remains uncertain. This study addresses the evidence of statin therapy on ICH and other clinical outcomes in patients with previous ischaemic stroke (IS) or ICH. METHODS: A systematic literature review and meta-analysis was performed in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to assess observational and randomised studies comparing statin therapy with control (placebo or no treatment) in patients with a previous ICH or IS. The risk ratios (RR) for the primary outcome (ICH) and secondary outcomes (IS, any stroke, mortality and function) were pooled using random effects meta-analysis according to stroke subtype. RESULTS: Forty-three studies with a combined total of 317 291 patient-years of follow-up were included. In patients with previous ICH, statins had no significant impact on the pooled RR for recurrent ICH (1.04, 95% CI 0.86 to 1.25; n=23 695); however, statins were associated with significant reductions in mortality (RR 0.49, 95% CI 0.36 to 0.67; n=89 976) and poor functional outcome (RR 0.71, 95% CI 0.67 to 0.75; n=9113). In patients with previous IS, statins were associated with a non-significant increase in ICH (RR 1.36, 95% CI 0.96 to 1.91; n=103 525), but significantly lower risks of recurrent IS (RR 0.74, 95% CI 0.66 to 0.83; n=53 162), any stroke (RR 0.82, 95% CI 0.67 to 0.99; n=55 260), mortality (RR 0.68, 95% CI 0.50 to 0.92; n=74 648) and poor functional outcome (RR 0.83, 95% CI 0.76 to 0.91; n=34 700). CONCLUSIONS: Irrespective of stroke subtype, there were non-significant trends towards future ICH with statins. However, this risk was overshadowed by substantial and significant improvements in mortality and functional outcome among statin users. TRIAL REGISTRATION NUMBER: CRD42017079863.

Early versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: multicentre cohort study.

BACKGROUND AND PURPOSE: The optimal time to start oral anticoagulant (OAC) in patients with ischaemic stroke due to non-valvular atrial fibrillation (AF) is unknown. We reviewed OAC timing in relation to 90-day clinical outcomes as a post hoc analysis from a prospective multicentre observational study. METHODS: We included patients with data on time to initiation of OAC from CROMIS-2 (Clinical Relevence Of Microbleeds In Stroke-2), a prospective observational inception cohort study of 1490 patients with ischaemic stroke or transient ischaemic attack (TIA) and AF treated with OAC. The primary outcome was the composite outcome of TIA, stroke (ischaemic stroke or intracranial haemorrhage) or death within 90 days of the qualifying stroke or TIA. We performed adjusted logistic regression analyses to compare early (0-4 days) and later (≥5 days or never started) OAC initiation. RESULTS: We included 1355 patients, mean age 76 (SD 10), 580 (43%) women. OAC was started early in 358 (26%) patients and later (or not at all) in 997 (74%) patients. The event rate within 90 days was 48/997 (5%) in the late-OAC group (2 intracranial haemorrhages, 18 ischaemic strokes or TIAs and 31 deaths (three deaths were as a result of new ischaemic strokes)) versus 7/358 (2%) in the early-OAC group (5 ischaemic strokes or TIAs and 2 deaths). In adjusted analyses, late OAC was not associated with the composite outcome (adjusted OR 1.17, 95% CI 0.48 to 2.84, p=0.736). CONCLUSION: In adjusted analyses, early OAC after acute ischaemic stroke or TIA associated with AF was not associated with a difference in the rate of the composite outcome of stroke, TIA or death at 90 days, compared with late OAC. However, despite adjustment for important baseline factors, patients selected for early OAC and late OAC might still have differed in important respects; evaluation of OAC timing in adequately powered randomised trials is required. CLINICAL TRIAL REGISTRATION: NCT02513316.

Cognitive Impairment Before Intracerebral Hemorrhage Is Associated With Cerebral Amyloid Angiopathy.

BACKGROUND AND PURPOSE: Although the association between cerebral amyloid angiopathy (CAA) and cognitive impairment is increasingly recognized, it is not clear whether this is because of the impact of recurrent intracerebral hemorrhage (ICH) events, disruptions caused by cerebral small vessel damage, or both. We investigated this by considering whether cognitive impairment before ICH was associated with neuroimaging features of CAA on magnetic resonance imaging. METHODS: We studied 166 patients with neuroimaging-confirmed ICH recruited to a prospective multicentre observational study. Preexisting cognitive impairment was determined using the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Magnetic resonance imaging markers of cerebral small vessel disease, including CAA, were rated by trained observers according to consensus guidelines. RESULTS: The prevalence of cognitive impairment before ICH was 24.7% (n=41) and, in adjusted analyses, was associated with fulfilling the modified Boston criteria for probable CAA at presentation (odds ratio, 4.01; 95% confidence interval, 1.53-10.51; P=0.005) and a higher composite CAA score (for each point increase, odds ratio, 1.42; 95% confidence interval, 1.03-1.97; P=0.033). We also found independent associations between pre-ICH cognitive decline and the presence of cortical superficial siderosis, strictly lobar microbleeds, and lobar ICH location, but not with other neuroimaging markers, or a composite small vessel disease score. CONCLUSIONS: CAA (defined using magnetic resonance imaging markers) is associated with cognitive decline before symptomatic ICH. This provides evidence that small vessel disruption in CAA makes an independent contribution to cognitive impairment, in addition to effects due to brain injury caused directly by ICH. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02513316.

MRI-visible perivascular space location is associated with Alzheimer's disease independently of amyloid burden.

Perivascular spaces that are visible on magnetic resonance imaging (MRI) are a neuroimaging marker of cerebral small vessel disease. Their location may relate to the type of underlying small vessel pathology: those in the white matter centrum semi-ovale have been associated with cerebral amyloid angiopathy, while those in the basal ganglia have been associated with deep perforating artery arteriolosclerosis. As cerebral amyloid angiopathy is an almost invariable pathological finding in Alzheimer's disease, we hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with a clinical diagnosis of Alzheimer's disease, whereas those in the basal ganglia would be associated with subcortical vascular cognitive impairment. We also hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with brain amyloid burden, as detected by amyloid positron emission tomography using 11C-Pittsburgh B compound (PiB-PET). Two hundred and twenty-six patients (Alzheimer's disease n = 110; subcortical vascular cognitive impairment n = 116) with standardized MRI and PiB-PET imaging were included. MRI-visible perivascular spaces were rated using a validated 4-point visual rating scale, and then categorized by severity ('none/mild', 'moderate' or 'frequent/severe'). Univariable and multivariable regression analyses were performed. Those with Alzheimer's disease-related cognitive impairment were younger, more likely to have a positive PiB-PET scan and carry at least one apolipoprotein E ɛ4 allele; those with subcortical vascular cognitive impairment were more likely to have hypertension, diabetes mellitus, hyperlipidaemia, prior stroke, lacunes, deep microbleeds, and carry the apolipoprotein E ɛ3 allele. In adjusted analyses, the severity of MRI-visible perivascular spaces in the centrum semi-ovale was independently associated with clinically diagnosed Alzheimer's disease (frequent/severe grade odds ratio 6.26, 95% confidence interval 1.66-23.58; P = 0.017, compared with none/mild grade), whereas the severity of MRI-visible perivascular spaces in the basal ganglia was associated with clinically diagnosed subcortical vascular cognitive impairment and negatively predicted Alzheimer's disease (frequent/severe grade odds ratio 0.03, 95% confidence interval 0.00-0.44; P = 0.009, compared with none/mild grade). MRI-visible perivascular space severity in either location did not predict PiB-PET. These findings provide further evidence that the anatomical distribution of MRI-visible perivascular spaces may reflect the underlying cerebral small vessel disease. Using MRI-visible perivascular space location and severity together with other imaging markers may improve the diagnostic value of neuroimaging in memory clinic populations, in particular in differentiating between clinically diagnosed Alzheimer's and subcortical vascular cognitive impairment.

Novel imaging techniques in cerebral small vessel diseases and vascular cognitive impairment.

Dementia is a global growing concern, affecting over 35 million people with a global economic impact of over $604 billion US. With an ageing population the number of people affected is expected double over the next two decades. Vascular cognitive impairment can be caused by various types of cerebrovascular disease, including cortical and subcortical infarcts, and the more diffuse white matter injury due to cerebral small vessel disease. Although this type of cognitive impairment is usually considered the second most common form of dementia after Alzheimer's disease, there is increasing recognition of the vascular contribution to neurodegeneration, with both pathologies frequently coexisting. The aim of this review is to highlight the recent advances in the understanding of vascular cognitive impairment, with a focus on small vessel diseases of the brain. We discuss recently identified small vessel imaging markers that have been associated with cognitive impairment, namely cerebral microbleeds, enlarged perivascular spaces, cortical superficial siderosis, and microinfarcts. We will also consider quantitative techniques including diffusion tensor imaging, magnetic resonance perfusion imaging with arterial spin labelling, functional magnetic resonance imaging and positron emission tomography. As well as potentially shedding light on the mechanism by which cerebral small vessel diseases cause dementia, these novel imaging biomarkers are also of increasing relevance given their ability to guide diagnosis and reflect disease progression, which may in the future be useful for therapeutic interventions. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice.

Cerebral amyloid angiopathy (CAA) has never been more relevant. The last 5 years have seen a rapid increase in publications and research in the field, with the development of new biomarkers for the disease, thanks to advances in MRI, amyloid positron emission tomography and cerebrospinal fluid biomarker analysis. The inadvertent development of CAA-like pathology in patients treated with amyloid-beta immunotherapy for Alzheimer's disease has highlighted the importance of establishing how and why CAA develops; without this information, the use of these treatments may be unnecessarily restricted. Our understanding of the clinical and radiological spectrum of CAA has continued to evolve, and there are new insights into the independent impact that CAA has on cognition in the context of ageing and intracerebral haemorrhage, as well as in Alzheimer's and other dementias. While the association between CAA and lobar intracerebral haemorrhage (with its high recurrence risk) is now well recognised, a number of management dilemmas remain, particularly when considering the use of antithrombotics, anticoagulants and statins. The Boston criteria for CAA, in use in one form or another for the last 20 years, are now being reviewed to reflect these new wide-ranging clinical and radiological findings. This review aims to provide a 5-year update on these recent advances, as well as a look towards future directions for CAA research and clinical practice.

Evaluation of I-Gel™ size 2 airway in different degrees of neck flexion in anesthetized children - a prospective, self-controlled trial.

BACKGROUND: A previous study by our group demonstrated an increase in oropharyngeal leak pressures and a deterioration of ventilation in maximum neck flexion with the I-Gel™ . To ascertain the optimal degree of neck flexion which increases OPLP without compromising ventilation we conducted a prospective self-controlled trial with the I-Gel™ in different degrees of neck flexion in anesthetized paralyzed children. METHODOLOGY: The I-gel™ was inserted in 60 children undergoing inhalation induction with muscle paralysis for routine general anesthesia. Recordings of peak inspiratory pressures (PIP) at flexion of 15°, 30°, and 45° were taken as the primary outcome. Expired tidal volume, ventilation scoring, fiberoptic gradings, and OPLP in different degrees of flexion were recorded as secondary outcomes. RESULTS: There was a significant increase in mean PIP in cm H2 O at flexion 30° [13.3 (95% CI 12.8-13.8) cm H2 O, P < 0.001] and 45° flexion (16.5 [15.9-17.1] cm H2 O, P < 0.001) compared to neutral. A decrease in the expired tidal volume was seen at flexion of 30° (7.6 [7.3-7.8] cm H2 O, P = 0.00) and 45° (7.6 [7.3-7.8] cm H2 O, P = 0.00). There was deterioration of ventilation score, mean [range] at 30° flexion 2[0-3], and 45° flexion 1[0-3] compared to the neutral 3[2-3]. There was a significant increase in OPLP with an increase in degree of flexion. CONCLUSION: We conclude that 15° neck flexion can safely be applied without compromising ventilation with the I-Gel™ in anesthetized paralyzed children. However, Flexion of 30° or more warrants caution or the use of alternative devices like an endotracheal tube due to increase in PIP and worsening of ventilation score.

Evaluation of I-gel™ airway in different head and neck positions in anesthetized paralyzed children.

BACKGROUND: Studies that have compared and quantified the oropharyngeal leak pressure (OPLP) and adequacy of ventilation with supraglottic airway devices in different head and neck positions have been done in adult populations. The effects of head-neck position changes on the functioning of I-gel(™) in pediatric population still remain unevaluated. AIM: This study aimed to quantify the influence of different head and neck positions namely neutral, maximum flexion, and maximum extension on OPLP, ventilation scoring, and fiberoptic grading using I-gel(™) in anesthetized, paralyzed children. METHODS: I-gel(™) was inserted in 30 paralyzed, anesthetized children scheduled for elective urological and orthopedic procedures. Anesthesia was induced with sevoflurane in oxygen. Atracurium was administered intravenously to facilitate neuromuscular relaxation. Recordings of OPLP in neutral, maximum flexion, and maximum extension were taken as primary outcome. Fiberoptic grading, insertion of ryle's tube and ventilation scoring were also measured in different head and neck positions as secondary outcomes. RESULTS: The OPLP was significantly higher in flexion (27.6 ± 3.3 cm H2 O, P = 0.000) and lower in extension (19.6 ± 3.2 cm H2 O, P = 0.006) in comparison to the neutral position (23.2 ± 3.2 cm H2 O). There was a worsening of the fiberoptic view in flexion compared to neutral position (0/5/19/6 vs 5/21/4/0). The ventilation score was poorer (1 [0-3], P < 0.05) and peak inspiratory pressures higher in flexion (15.2 ± 1.4 cm H2 O, P = 0.000) compared to the neutral position (10.4 ± 1.6 cm H2 O). CONCLUSION: Caution is warranted in pediatric patients while ventilating with I-gel(™) in extreme flexion of head and neck owing to poor ventilation despite increase in OPLP.