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Anatomy and physiology

Anatomy and physiology Perspectives 26 June 2020 Free

COVID‐19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre‐COVID‐19 ARDS

COVID‐19 ARDS is a predictable serious complication of COVID‐19 that requires early recognition and comprehensive management “This disease is still too strange to us, and there are too many doubts”, says Dr Ling Qin (LQ), after reviewing more than 400 patients with coronavirus disease 2019 (COVID‐19) pneumonia in Wuhan Union Hospital, China. COVID‐19 is a novel disease. We are familiar with acute respiratory distress syndrome (ARDS); however, when it occurs as part of COVID‐19, it has different features and there remain unanswered questions. So if someone has COVID‐19 ARDS, how does it compare and contrast with ARDS from other causes? To answer this question we provide a summary of the published literature (based on a PubMed search using the terms “COVID‐19” and “ARDS”, 17 April 2020) and current clinical experience from managing patients with COVID‐19 ARDS in Singapore (SHP) and Wuhan (LQ). Severe COVID‐19 represents viral pneumonia from severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection leading to ARDS. Its manifestations can be viewed as a combination of the two processes, namely viral pneumonia and ARDS. COVID‐19 is a novel disease recognised initially in Wuhan, China, in December 2019, and is now pandemic. It is likely caused by zoonotic spillover of a β‐coronavirus type 2b that is now transmitted between humans. Along with the other serious coronavirus infections of severe acute respiratory syndrome and Middle East respiratory syndrome, which also cause ARDS, COVID‐19 represents an ongoing global threat as this virus family has the potential to mutate and infect non‐immune populations. Australia's living guidelines provide the latest recommendations and evidence.1 Diagnosis SARS‐CoV‐2 infection can be confirmed by positive detection of viral RNA in nasopharyngeal secretions using a specific PCR test. COVID‐19 illness can be confirmed by a consistent clinical history, epidemiological contact, and a positive SARS‐CoV‐2 test. COVID‐19 ARDS is diagnosed when someone with confirmed COVID‐19 infection meets the Berlin 2012 ARDS diagnostic criteria2 of (i) acute hypoxaemic respiratory failure; (ii) presentation within 1 week of worsening respiratory symptoms; (iii) bilateral airspace disease on chest x‐ray, computed tomography (CT) or ultrasound that is not fully explained by effusions, lobar or lung collapse, or nodules; and (iv) cardiac failure is not the primary cause of acute hypoxaemic respiratory failure. ARDS is underdiagnosed in intensive care settings.3 ARDS develops in 42% of patients presenting with COVID‐19 pneumonia, and 61–81% of those requiring intensive care.4 COVID‐19 ARDS follows a predictable time course over days, with median time to intubation of 8.5 days after symptom onset in Singaporean patients.5 This is similar to previous reports where ARDS developed at day 8 or 9 after symptom onset. It is therefore important to monitor patients for the development of ARDS as their COVID‐19 infection progresses. Respiratory rate and SpO2 are two important parameters for judging patients’ clinical condition and allowing early recognition of ARDS. A patient who fits any one of the following conditions may have severe disease and require further evaluation: respiratory rate ≥ 30 breaths/min; SpO2 ≤ 92%; and PaO2/FiO2 ≤ 300 mmHg. Blood tests can also be helpful. In Singapore, it was noted that raised C‐reactive protein levels and blood neutrophil counts along with lymphopenia were more common in patients requiring invasive mechanical ventilation for COVID‐19 ARDS.5 Lung pathology ARDS causes diffuse alveolar damage in the lung. There is hyaline membrane formation in the alveoli in the acute stage, and this is followed by interstitial widening and by oedema and then fibroblast proliferation in the organising stage. COVID‐19 ARDS causes the typical ARDS pathological changes of diffuse alveolar damage in the lung.6,7 As patients move through the course of their illness, the longer term outcomes of ARDS are being reported, with lung fibrosis appearing as part of COVID‐19 ARDS.8,9 A study reported that 17% of patients had fibrous stripes in chest CT scans,9 and considered that the fibrous lesions may form during the healing of pulmonary chronic inflammation or proliferative diseases, with gradual replacement of cellular components by scar tissues. Thrombosis Pulmonary thrombosis is common in sepsis‐induced ARDS. Coagulation dysfunction appears to be common in COVID‐19, and is detected by elevated D‐dimer levels. In fatal cases there is diffuse microvascular thrombosis, suggesting a thrombotic microangiopathy, and most deaths from COVID‐19 ARDS have evidence of thrombotic disseminated intravascular coagulation.10 This may explain some of the atypical or unexpected manifestations seen in the lung, such as dilated pulmonary vessels on chest CT, and episodes of pleuritic pain. Vascular enlargement is rarely reported in typical ARDS, yet was seen in most cases of COVID‐19 ARDS.9 Mortality COVID‐19 ARDS appears to have worse outcomes than ARDS from other causes. The intensive care unit and hospital mortality from typical ARDS are 35.3% (95% CI, 33.3–37.2%) and 40.0% (95% CI, 38.1–42.1%), respectively.3 For COVID‐19 ARDS, mortality ranged between 26% and 61.5% if ever admitted into a critical care setting, and in patients who received mechanical ventilation, the mortality can range between 65.7% to 94%.4 Risk factors for poor outcomes include older age; presence of comorbidities such as hypertension, cardiovascular disease and diabetes mellitus; lower lymphocyte counts; kidney injury; and raised D‐dimer levels. Death from COVID‐19 ARDS is due to respiratory failure (53%), respiratory failure combined with cardiac failure (33%), myocardial damage and circulatory failure (7%), or death from an unknown cause.4 Radiology The radiology of ARDS is distinctive, yet COVID‐19 pneumonia appears to have unique features. This likely results from the co‐occurrence of viral pneumonia and ARDS, and allows radiologists to be fairly specific in diagnosing COVID‐19 pneumonia. The most discriminating features for COVID‐19 pneumonia in China compared with viral pneumonia in the United States included a peripheral distribution of opacification (80% v 57%; P < 0.001), frosted glass opacities (91% v 68%; P < 0.001), and vascular thickening or enlargement (58% v 22%; P < 0.001).11 These imaging features appear to be typical for COVID‐19 pneumonia and can be helpful in early screening of highly suspected cases and in evaluation of the severity and extent of disease. As COVID‐19 lung disease progresses, the lesions are more likely to be bilateral, lower lung predominant and multifocal. They often have the appearance of rounded opacities, termed “COVID balls”. With the development of ARDS, the extent of lung involvement increases, and there is a consolidative component.12 The opacities resolve with recovery from COVID‐19;13 however, with ARDS, the lesions increase in their extent and density, and evolve to fibrotic bands. Ventilation The strategy of breathing support is very important in treating COVID‐19 ARDS, as is the case with typical ARDS caused by other pathogens.14 The key elements are: use oxygen by nasal cannulae to achieve SpO2 > 92%; use of high flow nasal oxygen is controversial and highly dependent on the treatment location; avoid non‐invasive ventilation; prone ventilation appears to be beneficial; and consider extracorporeal membrane oxygenation for rescue. Because of concerns about viral transmission to other patients and health care workers,15 the use of high flow nasal oxygen and non‐invasive ventilation (such as bi‐level positive pressure ventilation) for COVID‐19 ARDS is highly dependent on the health care setting. Australian COVID‐19 guidelines1 strongly recommend against the use of high flow nasal oxygen in emergency departments, but provide a strong recommendation for its use in negative pressure single rooms. Non‐invasive ventilation may be used in negative pressure rooms with appropriate viral transmission precautions.1 Clinical experience has found inconsistent benefit from non‐invasive ventilation and there is concern about aerosol generation and increased risk of viral transmission. Prone ventilation appears to be beneficial for COVID‐19 ARDS.1 Placing a person in prone position promotes more homogenous aeration of the lung in ARDS and can improve oxygenation. While prone ventilation is used in only about 16% of patients with typical ARDS,3,16 in COVID‐19 it is being used successfully earlier in the course of ARDS, and suggested use is for > 12 hours per day.16 Venovenous extracorporeal membrane oxygenation can be used as rescue for mechanically ventilated adults with COVID‐19 and hypoxaemia that persists despite optimised ventilation, use of rescue therapies and prone ventilation. Among critically ill patients treated in Wuhan, prone ventilation and extracorporeal membrane oxygenation treatment were not found to be as effective as for ARDS caused by other pathogens. Possible reasons include: COVID‐19 pneumonia was still progressing and was not under control; lung lesions were not completely gravity‐dependent under ultrasound, so the effect of the prone position was limited; the patient's immune status was not restored, and a secondary hospital‐acquired infection worsened the condition; and when case numbers are high from the epidemic, the management mode and human resource arrangement of the isolation wards still need to be discussed and strengthened. Anecdotal observations in Singapore (SHP) and investigations in the Netherlands17 suggested that patients ventilated for COVID‐19 ARDS tended to have plateau pressures < 30 cmH20 and driving pressures < 15 cmH20 despite high oxygen requirements. The lung protective ventilation strategy used in typical ARDS involves a low tidal volume (6 mL/kg) and higher positive end expiratory pressure targets. For COVID‐19 ARDS, a change to more generous tidal volume targets allowing up to 8 mL/kg and lower positive end expiratory pressure levels is suggested to prevent patient self‐inflicted lung injury. Adjunct treatment In typical ARDS, continuous neuromuscular blocking agents, high dose corticosteroids and recruitment manoeuvers were the most frequently used adjunctive therapies. In COVID‐19 ARDS, the evidence for systemic steroids is still scarce and they are only recommended in patients with concomitant shock which has been unresponsive to vasopressors. There are concerns that steroids may increase viral shedding and possibly lead to a higher mortality rate. Antiviral therapy Many patients with COVID‐19 receive antiviral or immunosuppressive therapy. In Australia, the National COVID‐19 Clinical Evidence Taskforce1 recommends administering antiviral medications or other disease‐modifying treatments in the context of clinical trials. Singapore was using empiric lopinavir–ritonavir plus subcutaneous interferon‐β 1b initially, but is now randomising patients to receive remdesivir. In Wuhan, a broad range of antiviral and immune therapies are being used. All patients also received treatment with Chinese medicine. COVID‐19 ARDS is a predictable serious complication of COVID‐19 that requires early recognition and comprehensive management. Research programs such as the Medical Research Future Fund 2020 Respiratory Medicine Clinical Trials Research on COVID‐19 grant opportunity are required to answer the important questions that remain about therapies for COVID‐19 ARDS.

Peter G Gibson · Ling Qin · Ser Hon Puah

Mja2 50674
Anatomy and physiology Perspective 9 March 2020 Free

Breathing life into Australian diabetes clinical guidelines

Living guidelines that incorporate new evidence as it becomes available have the potential to overcome some of the limitations inherent in static guidelines Diabetes is a complex chronic condition that affects about 1.7 million Australians and represents an estimated $15 billion per annum in direct and indirect costs to the Australian economy.1 Almost $215 million of subsidies were delivered during the 2015–16 financial year to the 1.32 million registrants of the National Diabetes Services Scheme, an Australian Government initiative that provides support to Australians living with diabetes. In 2019, an additional $100 million was announced for funding the Continuous Glucose Monitoring Initiative, which provides fully subsidised continuous glucose monitoring products to patients with diabetes who meet certain criteria.2 In 2017, almost 1.2 million hospitalisations and 11% of all deaths in Australia listed diabetes as the principal or associated cause.3 In addition to the costs associated with diabetes management and prevention, significant funding has been directed towards research into this key priority area, with the National Health and Medical Research Council (NHMRC) providing $375 million from 2013–2018 towards efforts to improve the prevention, diagnosis and management of diabetes.4 With the objective of strengthening diabetes policy and practice, the Australian Government developed the Australian National Diabetes Strategy 2016–2020, which outlines an integrated and coordinated approach for reducing the social, human and economic impact of diabetes.5 One of the key goals within this strategy involves strengthening prevention and care through the use of research, evidence and data. Indeed, developing a nationally endorsed set of diabetes guidelines, assessed against the clinical practice guidelines criteria, was a key recommendation of the Australian National Diabetes Strategy to improve complications and outcomes associated with the disease. Producing new clinical guidelines and implementing a system by which recommendations can be updated and adopted rapidly represents an important means by which this recommendation can be achieved. Clinical guidelines: is there a better way? High quality, evidence‐based clinical guidelines are integral to ensuring that health care decisions are based on the best available evidence. Unfortunately, evidence‐based clinical guideline development is an expensive and laborious undertaking in which several years can pass between inception and publication. In Australia, guidelines approved by the NHMRC are valid for 5 years from publication before they are considered outdated, following which they must be either updated or developed anew.6 These delays can result in several potential problems. First, new research is continually being generated throughout the development period, which may mean that a guideline is outdated before it is even published. Indeed, it has been demonstrated that one in five guideline recommendations are outdated within 3 years of guideline publication.7 Second, institutional memory of the decision‐making processes through which recommendations are derived can be lost, particularly if a significant period of time has transpired since the original guideline was developed. Third, changes in the policy and practice environment can shift priorities or raise new questions that were not considered when defining the original scope, resulting in the guideline failing to address some of the key current issues relating to the topic of interest (eg, the development of a new therapeutic or withdrawal of a technology from the Australian Register of Therapeutic Goods). Currently, all but one of the NHMRC‐approved diabetes clinical guidelines are outdated and have been rescinded. As a result, there is no up‐to‐date Australian guidance for clinicians caring for people with diabetes, potentially resulting in the suboptimal management and significant variation in care of this condition.8 Living guidelines Living guidelines represent an approach to guideline development in which individual recommendations are continually updated as new, relevant evidence becomes available. This is achieved through monthly searches of key databases to identify recently published research. Following analysis of the new data, an impact assessment is conducted to determine whether the evidence is of sufficient relevance, reliability and importance to justify revising recommendations.9 Updated recommendations are then published within a real‐time digital dissemination platform, providing stakeholders with access to the most up‐to‐date version of the guideline. Although the concept of living guidelines is not new, many of the processes employed in developing living guidelines have been generated through Project Transform, an innovative platform established by Cochrane to address the critical issue of evidence currency within clinical guidelines (https://community.cochrane.org/help/tools-and-software/project-transform/about-project-transform). These processes are supported by the development and refinement of machine learning algorithms (eg, randomised controlled trial classifiers), citizen science initiatives (eg, Cochrane Crowd), new methods for updating statistical analyses,10,11 and the development of online collaborative platforms for systematic review and clinical practice guideline production (eg, Covidence, MAGICApp). The application of these tools significantly reduces the workload of systematic review and guideline authors, and appears to result in the production of updated recommendations at a fraction of the resource and time costs otherwise required. In addition, the establishment of a living guideline development group improves the retention of institutional memory throughout the process of updating, and the feedback mechanisms built into the process provide a means by which the underlying scope can be adapted to changes in policy and practice in Australia (Box 1). Living evidence for diabetes Embracing the inherent potential in living guidelines, the Living Evidence for Diabetes Consortium is developing living guidelines that address key priorities relating to diabetes prevention, diagnosis and management (https://livingevidence.org.au/new-index-3#Living-Guidelines-for-Diabetes). Consisting of the Australian Diabetes Society, Diabetes Australia, the Australasian Paediatric Endocrine Group, the Australian Diabetes Educators Association and Cochrane Australia, with representation from the Royal Australian College of General Practitioners and the Australian Government Department of Health, the consortium has selected two proof‐of‐concept topics that fulfil the criteria for living guidelines (Box 2). Two systematic reviews are currently under development to underpin these guidelines, focused on the comparative safety and effectiveness of therapeutics for blood glucose control in adults with type 2 diabetes and the use of technologies (such as insulin pumps and continuous glucose monitors) for the management of type 1 diabetes in adult and paediatric populations. The need for clear guidance relating to these topics is demonstrated by the ongoing uncertainty regarding the most appropriate choice of second line therapies13 and the inception of do‐it‐yourself closed loop systems.14 Although the methods and processes required to produce living guidelines are still evolving, the development of living guidelines for diabetes represents a paradigm shift in the way recommendations are updated and shared with decision makers. Access to this resource should improve the likelihood that patients will consistently receive the best evidence‐based care available, and also provide an avenue through which guideline developers can respond to changes in policy and practice, resulting in guidelines that evolve to keep up with the current practice. Box 1 – Static guideline development (A) versus living guideline development (B) Box 2 – Requirements for converting traditional to living recommendations12 Not all recommendations are suitable for a living evidence approach. Three key requirements should be fulfilled to justify transitioning a static guideline into a living guideline: the guideline should focus on a priority topic for patient, clinical or policy decision‐making; uncertainty should exist regarding the strength and/or direction of recommendations; and there should be a high likelihood of new evidence becoming available in the near future which could increase certainty.

Heath White · Britta Tendal · Julian Elliott · Tari Turner · Sofianos Andrikopoulos · Sophia Zoungas

Mja2 50509
Neurology Letters 4 November 2019 Free

Vitamin B12 supplementation futile for preventing demyelination in ongoing nitrous oxide misuse

To the Editor: Recreational misuse of nitrous oxide remains a significant public health problem,1 sustained in part by the ready availability online of gas‐containing canisters intended for use in the catering industry. Known as “nangs” or “whippits” and usually purchased in bulk, each canister contains 8 g of nitrous oxide. When inhaled, this gives a seconds‐long “high”, which is typically prolonged by using several “nangs” in a single session. Some individuals can consume hundreds each day. Prolonged exposure to nitrous oxide leads to the oxidisation of vitamin B12, rendering it unusable in key enzymatic reactions necessary for normal myelin synthesis.2 Over time, this leads to a potentially devastating neuropsychiatric syndrome that commonly presents with ataxia.3 Notably, the culprit shortage of vitamin B12 is a qualitative one and can be purely so, meaning that marked clinical deficits emerge in the presence of serum B12 levels that appear normal on standard laboratory assays. Furthermore, with continued exposure to nitrous oxide, these deficits will respond poorly to vitamin B12 supplementation. In a year‐long clinical audit at Royal Prince Alfred Hospital (2017–2018), seven nitrous oxide users, all aged between 20 and 30 years, presented with ataxia that ranged from mild to severe (Box 1). Most patients also had psychiatric symptoms. Nearly every patient estimated using 100 or more canisters of nitrous oxide per day in the months before being seen. Four patients also reported engaging in B12 supplementation (both oral and parenteral), aiming to circumvent the harmful sequelae of prolonged nitrous oxide misuse. Laboratory studies showed that all seven patients had accumulated homocysteine, as is usually seen when vitamin B12 is in short supply in the body.2 Individuals who reported taking supplements had serum B12 levels that were either normal or in excess of normal, implicating a qualitative deficiency of metabolically useful B12. Evidence of demyelination was seen on spinal cord imaging in six patients, including all those who used supplements, with the “inverted V” sign4 visible on T2‐weighted magnetic resonance imaging sequences (Box 2). Despite treatment according to best practice guidelines, all patients left hospital with persistent symptoms, and most were unable to walk or to attend to their bodily needs without the assistance of family members (modified Rankin score, 4). Sadly, one of the least affected individuals re‐presented to hospital with worsened symptoms because of continued nitrous oxide misuse. At every opportunity nitrous oxide users should be reminded of the futility of B12 supplementation, as one of many reasons why they should choose to avoid this profoundly destructive drug. Box 1 – Patients presenting with symptoms due to nitrous oxide misuse Age (years) Sex Canister use Duration of use B12 supplementation Ataxia severity* Psychiatric symptoms† Homocysteine level Serum B12 (active) MRI: “inverted V” sign‡ mRS: Day 1 mRS: discharge 20 Female 250/day 1 year No Severe Yes High Low (low) Yes 4 4 30 Male 60/day 1 year No Moderate Yes High Low (low) Yes 1 1 30 Male 100/day 6 months No Mild No High Low (normal) No 1 1 21 Male 200/day 1 year Yes Severe Yes High Normal (normal) Yes 4 4 23 Female 300/day 2 months Yes Severe Yes High Normal (high) Yes 4 4 23 Female 200/day 2 months Yes Severe Yes High High (high) Yes 4 4 28 Male 300/day 1 year Yes Mild No High Normal (normal) Yes 1 1 MRI = magnetic resonance imaging; mRS = modified Rankin score of neurological disability. * Ataxia: mild = visible gait disturbance; moderate = frequent falls; severe = inability to walk without assistance. † Psychiatric symptoms included mood disturbance, memory impairment and psychosis. ‡ MRI findings: “inverted V” sign on T2‐weighted MRI spinal cord imaging (Box 2). mRS: 0 = no symptoms; 1 = no significant disability despite symptoms; 2 = slight disability; 3 = moderate disability; 4 = moderately severe disability, unable to walk or attend to bodily needs without assistance; 5 = severe disability, bedridden; 6 = dead. Box 2 – T2‐weighted magnetic resonance imaging sequence showing “inverted V” sign, indicating the presence of dorsal column demyelination

Christopher Blair · Chris Tremonti · Leon Edwards · Paul S Haber · G Michael Halmagyi

Mja2 50371

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