We present a rare case of a 2-year-old male patient referred for primary evaluation of constipation and ultimately treatment of Hirschsprung disease (HSCR) whose preoperative workup incidentally revealed a posterior paraspinal mass. Following the biopsy of the mass, the patient exhibited hypoventilation and hypoxia requiring a delayed extubation, raising suspicion for congenital central hypoventilation syndrome (CCHS). We focus on the known history of associations between HSCR and CCHS, in addition to recently found genetic mutations in paired-like homeobox 2B that link HSCR, CCHS, and neuroblastoma.

Although mechanical ventilation can be a complex and seemingly elusive topic, expectations are that physicians and healthcare professionals who deal with critically ill patients have a basic familiarity with the management of a patient on a ventilator. Additionally, providers must also understand how applying mechanical ventilation affects patient physiology and response to disease states. The focus of this article will be on the management of the intubated patient in the first few hours of care on mechanical ventilation. It will review the basics of mechanical ventilation.  The primary indications for mechanical ventilation are:[1]: 1. Airway protection in a patient who is obtunded or has a dynamic airway, e.g., from trauma or oropharyngeal infection. 2. Hypercapnic respiratory failure due to a decrease in minute ventilation. 3. Hypoxemic respiratory failure due to a failure of oxygenation. 4. Cardiovascular distress whereby mechanical ventilation can offload the energy requirements of breathing. 5. Expectant course, e.g., anticipated patient decline or impending transfer.

Hyperventilation syndrome (HVS) is a common source of dyspnea and disability. While pulmonary rehabilitation (PR) including breathing exercises is indicated, randomized controlled trial are warranted to recommend one type of breathing exercise than another. We aimed to compare during PR, the effect of 5 sessions of nasal ventilation exercise (NV+PR) versus voluntary hypoventilation (vHV+PR) on exercise dyspnea (primary outcome) and capacity and health-related quality of life in patients. In this open label randomized controlled trial, 19 HVS patients (age=48.3 ± 15.2 y.o, female/male=18/1, Nijmegen score=33 ± 7.7) were randomized in a NV+PR (n = 9) or vHV+PR (n = 10) group. Modified Medical Research Council (mMRC) dyspnea, 6-minute walking distance (6MWD) with nasal/oral ventilation were assessed before and after 3 months of PR, and questionnaires (Nijmegen, VQ-11). There was a significant effect of PR of but no significant difference between groups in the improvements of dyspnea@max exercise (time effect (T): p < 0.01; group (G): p = 0.63; group*time interaction (G*T): p = 0.49), mMRC dyspnea (T: p < 0.01; G: p = 0.45; G*T: p = 0.62), 6MWD (T: p < 0.05; G: p = 0.36; G*T: p = 0.31), VQ-11 (T: p < 0.001; G: p = 0.16; G*T: p = 0.09) and plasma HCO3- (T: p < 0.05; G: p = 0.93; G*T; p = 0.36), Yet, Nijmegen score (T: p < 0.01; G: p = 0.32; G*T: p < 0.05) improvement was larger in NV+PR group. The exercise oronasal breathing shift during the 6MWT was significantly delayed in all patients (T: p < 0.05; G: p = 0.30; G*T: p = 0.32) and positively correlated with plasma HCO3-(r = 0.42; p < 0.05). Nasal exercise was not superior versus voluntary hypoventilation during PR in HVS patients. Yet, nasal exercise appeared feasible, leading to acquisition of a nasal breathing pattern during walking, improvement of PR outcomes and ventilatory alkalosis. The link between nasal breathing and hyperventilation is discussed in the light of the nasal ventilation rhythm in the limbic system and its role on the limbic emotional and ventilatory functions.

Current guidelines recommend that patients with obesity hypoventilation syndrome (OHS) are electively admitted for inpatient initiation of home non-invasive ventilation (NIV). We hypothesised that outpatient NIV setup would be more cost-effective.

Positive airway pressure (PAP) is the primary treatment of sleep-disordered breathing including obstructive sleep apnea, central sleep apnea, and sleep-related hypoventilation. Just as clinicians use pharmacological mechanism of action and pharmacokinetic data to optimize medication therapy for an individual, understanding how PAP works and choosing the right mode and device are critical to optimizing therapy in an individual patient. The first section of this chapter will describe the technology inside PAP devices that is essential for understanding the algorithms used to control the airflow and pressure. The second section will review how different comfort settings including ramp and expiratory pressure relief and modes of PAP therapy including continuous positive airway pressure (CPAP), autotitrating CPAP, bilevel positive airway pressure, adaptive servoventilation, and volume-assured pressure support control the airflow and pressure. Proprietary algorithms from several different manufacturers are described. This chapter derives its descriptions of algorithms from multiple sources including literature review, manufacture publications and websites, patents, and peer-reviewed device comparisons and from personal communication with manufacturer representatives. Clinical considerations related to the technological aspects of the different algorithms and features will be reviewed.

We present a neonate with early onset apnea and bradycardia in the absence of primary cardiorespiratory and central nervous system disorders that eventually required chronic ventilator support starting at 6 hours of life. Molecular testing of paired-like homeobox 2b (PHOX2B) gene mutation confirmed the diagnosis of congenital central hypoventilation syndrome (CCHS). CCHS is a rare genetic disorder characterized by impaired central respiratory control with or without broad spectrum of autonomic nervous system (ANS) dysregulations. Ocular ANS dysregulation is a rare finding in CCHS individuals, and it is usually discovered later in life. However, the ophthalmic evaluation of this neonate on first day of life revealed persistent mild dilated oval pupils with limited light reactivity.

Acute respiratory failure is caused by a wide range of etiologies.  Progression to cardiopulmonary arrest and ultimately death is likely in the absence of effective and timely airway management. Therefore, one of the primary goals of airway management is to provide adequate ventilation and oxygenation to avoid or halt the progression to cardiopulmonary arrest. Effective and timely airway management is also an essential component of successful cardiopulmonary resuscitation. Airway management is critical in the pediatric population as pediatric airway problems are commonly seen in pediatric and general emergency departments. Respiratory distress is the fourth most common chief complaint in children presenting to the emergency department.[1][2][3] Initial steps in airway management include airway positioning maneuvers (for example, head-tilt-chin lift, jaw-thrust), suctioning, supplemental oxygen, and re-positioning of the airway if the previous steps are ineffective. Airway positioning maneuvers place the airway in a neutral position and help move the tongue and palatal tissues away from the posterior wall of the pharynx. When choosing an airway positioning maneuver, one must be cognizant of the possible presence or absence of a cervical spine injury. Suctioning assists with the removal of secretions that could be causing or contributing to airway obstruction. If these steps do not help in maintaining a patent airway or in providing adequate ventilation and oxygenation, then an airway adjunct should be utilized. Airway adjuncts are used to relieve or bypass an upper airway obstruction during airway management. However, upper airway obstruction may be present for several reasons, and airway adjuncts may not be able to relieve or bypass all types of obstruction. Upper airway obstruction may occur from anatomical causes such as choanal atresia, pathological causes such as a tonsillar abscess or adverse effects from patient management such as loss of airway patency during the administration of sedation and/or analgesia.[4][5] There are also subsets of patients that are more prone to develop upper airway obstruction. Patients with obesity are at significant risk for upper airway obstruction due to altered upper airway anatomy. Pharyngeal tissues have increased fat deposition causing excess upper airway tissue and an increased likelihood of pharyngeal wall collapse resulting in airway obstruction. This can be exacerbated when patients with obesity are given drugs that depress the central nervous system or have other co-morbidities, such as obstructive sleep apnea (OSA) and/or obstructive hypoventilation syndrome (OHS). The presence of OSA and/or OHS can be associated with increased sensitivity to the respiratory depressant effects of sedatives and opioids increasing the tendency to obstruct the airway. Pediatric patients, in particular infants and young children, are susceptible to upper airway obstruction. This predisposition is due to the differences between pediatric and adult airways. Infants and young children have a relatively large occiput that causes neck flexion when lying supine. This results in a natural tendency to obstruct the upper airway. They have a proportionally large tongue relative to the size of their oral cavity which also causes a natural obstruction of the airway. Additionally, a shortened thyromental distance in this patient population brings the tongue into proximity of the soft palate. Consequently, this leads to obstruction of the airway. Lastly, compared to adults, infants and young children have larger adenoidal tissue, as well as, more distensible and compliant larger airways which predisposes them to airway obstruction. In general, by the age of eight, the pediatric airway is very similar to that of an adult airway. There are two types of airway adjuncts. One is an oropharyngeal airway, and the other is a nasopharyngeal airway. This article will summarize the former.

The autonomic nervous system (ANS) plays an important role in the coordination of several physiological functions including sleep/wake process. Significant changes in ANS activity occur during wake-to-sleep transition maintaining the adequate cardiorespiratory regulation and brain activity. Since sleep is a complex homeostatic function, partly regulated by the ANS, it is not surprising that sleep disruption trigger and/or evidence symptoms of ANS impairment. Indeed, several studies suggest a bidirectional relationship between impaired ANS function (i.e. enhanced sympathetic drive), and the emergence/development of sleep disorders. Furthermore, several epidemiological studies described a strong association between sympathetic-mediated diseases and the development and maintenance of sleep disorders resulting in a vicious cycle with adverse outcomes and increased mortality risk. However, which and how the sleep/wake control and ANS circuitry becomes affected during the progression of ANS-related diseases remains poorly understood. Thus, understanding the physiological mechanisms underpinning sleep/wake-dependent sympathetic modulation could provide insights into diseases involving autonomic dysfunction. The purpose of this review is to explore potential neural mechanisms involved in both the onset/maintenance of sympathetic-mediated diseases (Rett syndrome, congenital central hypoventilation syndrome, obstructive sleep apnoea, type 2 diabetes, obesity, heart failure, hypertension, and neurodegenerative diseases) and their plausible contribution to the generation of sleep disorders in order to review evidence that may serve to establish a causal link between sleep disorders and heightened sympathetic activity.

It has been reported that the manual chest compression and decompression (MCCD) maneuver can increase lung volume in patients receiving invasive mechanical ventilation (IMV), but some important questions related to this maneuver require answers: how long the effects of MCCD on lung volume remain, and whether there are effects on other respiratory and hemodynamic variables.

Respiratory acidosis is a state in which there is usually a failure of ventilation and an accumulation of carbon dioxide. The primary disturbance of elevated arterial PCO2 is the decreased ratio of arterial bicarbonate to arterial PCO2, which leads to a lowering of the pH. In the presence of alveolar hypoventilation, 2 features commonly are seen are respiratory acidosis and hypercapnia. To compensate for the disturbance in the balance between carbon dioxide and bicarbonate (HCO3-), the kidneys begin to excrete more acid in the forms of hydrogen and ammonium and reabsorb more base in the form of bicarbonate. This compensation helps to normalize the pH.[1]

Central sleep apnea (CSA) is characterized by transient diminution or cessation of the respiratory rhythm generator located within the pontomedullary region of the brain. In general, CSA represents an array of sleep-disordered breathing (SDB) conditions due to the brief absence of ventilatory output during sleep. CSA manifests as a cyclical phenomenon/pattern during sleep; periods of apnea or hypopnea alternating with hyperpnea. Although there is a lack of effort during central events, it has been found that the upper airway narrows or nearly collapses during these events. Upper airway narrowing consistently occurs at the retropalatal level during induced hypocapnic central apnea (video 1) and induced central hypopnea.[1]  Though the prevalence of CSA is lower than OSA, both conditions often coexist, and patients can exhibit features of both states. The International Classification of Sleep Disorders – Third Edition (ICSD-3) [2] has divided CSA syndromes into several categories based on distinct clinical and polysomnographic features; 1. Primary CSA. 2. CSA with Cheyne-Stokes Breathing (CSB). 3. CSA due to a medical disorder without CSB. 4. CSA due to a periodic high-altitude breathing. 5. CSA due to a medication or substance. 6. Treatment-emergent CSA. Both hypoventilation and hyperventilation can result in central apneas, and each one acts through a distinct pathophysiological pathway. Thus, the degree of alveolar ventilation often serves as a basis for an alternate classification of CSA. Patients with heart failure are often hypocapnic during wakefulness and have an increased propensity to develop hyperventilation related CSA; however, hypoventilation related CSA commonly occur in neuromuscular diseases (amyotrophic lateral sclerosis, brainstem stroke), overuse of medications with side effects of central nervous system depression (opioids), cervical spinal cord injury and structural abnormalities affecting pulmonary dynamics (kyphoscoliosis).[3][4]

Obstructive sleep apnoea syndrome (OSA) in paediatrics is a rather frequent pathology caused by pathophysiological alterations leading to partial and prolonged obstruction (hypoventilation) and/or intermittent partial (hypopnoea) or complete (apnoea) obstruction of the upper airways. Paediatric OSA is characterised by daytime and night-time symptoms. Unfortunately, there are few data on shared diagnostic-therapeutic pathways that address OSA with a multidisciplinary approach in paediatric age. This document summarizes recommendations from the Emilia-Romagna Region, Italy, developed in order to provide the most appropriate tools for a multidisciplinary approach in the diagnosis, treatment and care of paediatric patients with OSA. The multidisciplinary group of experts distinguished two different 'step' pathways, depending on the age group considered (i.e., under or over two years). In most cases, these pathways can be carried out by the primary care paediatrician, who represents the first filter for approaching the problem. For this reason, it is essential that the primary care paediatrician receives adequate training on how to formulate the diagnostic suspicion of OSA and on what criteria to use to select patients to be sent to the hospital centre. The relationship between the paediatrician of the patient and her/his parents must see a synergy of behaviour between the various players in order to avoid uncertainty about the diagnostic and therapeutic decisions as well as the follow-up phase. The definition and evaluation of the organizational process and outcome indicators of the developed flow-chart, and the impact of its implementation will remain fundamental.

Metabolic alkalosis is a widespread acid-base disturbance, especially in hospitalized patients. It is characterized by the primary elevation of serum bicarbonate and arterial pH, along with a compensatory increase in Pco2 consequent to adaptive hypoventilation. The pathogenesis of metabolic alkalosis involves either a loss of fixed acid or a net accumulation of bicarbonate within the extracellular fluid. The loss of acid may be via the gastrointestinal tract or the kidney, whereas the sources of excess alkali may be via oral or parenteral alkali intake. Severe metabolic alkalosis in critically ill patients-arterial blood pH of 7.55 or higher-is associated with significantly increased mortality rate. The kidney is equipped with sophisticated mechanisms to avert the generation or the persistence (maintenance) of metabolic alkalosis by enhancing bicarbonate excretion. These mechanisms include increased filtration as well as decreased absorption and enhanced secretion of bicarbonate by specialized transporters in specific nephron segments. Factors that interfere with these mechanisms will impair the ability of the kidney to eliminate excess bicarbonate, therefore promoting the generation or impairing the correction of metabolic alkalosis. These factors include volume contraction, low glomerular filtration rate, potassium deficiency, hypochloremia, aldosterone excess, and elevated arterial carbon dioxide. Major clinical states are associated with metabolic alkalosis, including vomiting, aldosterone or cortisol excess, licorice ingestion, chloruretic diuretics, excess calcium alkali ingestion, and genetic diseases such as Bartter syndrome, Gitelman syndrome, and cystic fibrosis. In this installment in the AJKD Core Curriculum in Nephrology, we will review the pathogenesis of metabolic alkalosis; appraise the precipitating events; and discuss clinical presentations, diagnoses, and treatments of metabolic alkalosis.

Stroke is one of the leading causes of death and long-term disability worldwide.[1][2] As medical management advances, the incidence and mortality rate of stroke declines, with most strokes presenting as ischemic strokes vs. hemorrhagic strokes. As such, the focus of this article will be on ischemic strokes. Various etiologies lead to ischemic stroke, including both modifiable and non-modifiable risk factors. Non-modifiable risks include age, sex, and race/ethnicity.[3] Whereas modifiable risk factors encompass: physical inactivity, waist-to-hip ratio, alcohol consumption, smoking, nutrition, hypertension, hyperlipidemia, diabetes mellitus, cardiac causes, such as atrial fibrillation (AF), and metabolic syndromes.[3][4][5] Moreover, short-term triggers may also pose a risk for stroke, including acute infectious processes, stress, etc. Assessing a patient’s risk for stroke based on risk factors is an important component of primary care for strokes. There are several validated risk stratification calculators used to assist in identifying patients needing preventative therapies. For instance, a recognized, continuously updated tool to predict clinical stroke is the Framingham Stroke Risk Profile, which combines both modifiable and non-modifiable risks.[3][6] Ultimately, targeted interventions can decrease the burden of stroke. Stroke rule out should be completed in patients presenting with altered consciousness or sudden, focal, or global neurological deficits. Time is of the essence in completing a thorough history and physical in patients presenting with stroke-like symptoms. Upon presentation, one of the most crucial steps is identifying the time of ischemic stroke symptoms onset, as that helps determine eligibility for antithrombotic treatment or endovascular intervention. Physical examination goals are to determine stroke location, distinguish stroke mimics, complete neurological deficit assessment, and identify comorbidities and conditions that can affect treatment. A clinician should complete a neurological assessment and baseline function calculated via the National Institutes of Health Stroke Scale (NIHSS). The history and physical examination should be used to rule out other mimics of stroke, including hyperglycemia, hypoglycemia, seizures, syncope, migraines, or drug toxicity, etc. A focused history should identify ischemic stroke risk factors discussed earlier in this article and identify any recent trauma, coagulopathies, oral contraceptives, illicit drug use such as cocaine, and migraines. The following merit consideration when starting therapy: non-contrast brain CT or MRI, blood glucose, and oxygen saturation. Further, all patients should also have baseline labs that include: complete blood count with platelet count, serum electrolytes/renal function, cardiac panel, activated partial thromboplastin time (APTT), prothrombin time/international normalized ratio (INR), and electrocardiogram (ECG); although it is desirable to know the results of the preceding labs, therapy should not be delayed while results are pending, the exception being if there is suspicion for thrombocytopenia or bleeding abnormalities, and use of heparin or warfarin or other anticoagulants. In patients with suspected stroke, an emergent non-contrast computed tomography (CT) is generally the first step in the diagnostic study to rule out any bleeding. The results of the CT will also help determine if the patient is a candidate for antithrombotic therapy. Magnetic resonance imaging (MRI) testing may also be used to identify intracerebral hemorrhaging and is more sensitive than CT for early detection of brain infarction. The essential lab before initiation of therapy is blood glucose, as hypoglycemia or hyperglycemia can mimic stroke.[7][8][9][10] The clinicians should also perform a vitals assessment focusing on respiration, temperature, and blood pressure upon presentation. Elevation in blood pressure could indicate the body’s response to maintain brain perfusion to the occluded section. Patients with hypoventilation can result in an increase in carbon dioxide partial pressure, which can further cause cerebral vasodilation and elevation in intracranial pressure (ICP), at which point there should be an assessment of the need for intubation. Finally, normothermia is important for the first few days post-acute stroke, as fever can worsen ischemia.[7][10] There are significant updates to literature that have come to the surface for effective and appropriate management of patients with ischemic stroke. The American Heart Association/American Stroke Association (AHA/ASA) has published guidelines, most recent being in 2018, outlining optimal treatment for the early management of patients with ischemic stroke. Ischemic stroke intervention includes the use of thrombolytic, anticoagulants, antiplatelet, statins, antihypertensive, and blood glucose management.[11] Previously, anticoagulation played a significant role in the acute treatment of ischemic stroke. Recent studies have helped refine their use and have restricted the start time of anticoagulation post-ischemic stroke to only certain patient populations. Anticoagulants now play a major role in the primary and secondary prevention of ischemic strokes.

The Japanese government's latest manual on COVID-19 management mentions non-invasive ventilation (NIV). Before this version, we experienced three cases in which COVID-19 was a concern. Each case had one of the following conditions: obesity hypoventilation syndrome, amyotrophic lateral sclerosis, acute heart failure with acute kidney injury with hypercapnia. The guidelines indicate that patients with these diseases are good candidates for NIV. NIV was used in a negative pressure room with staff in personal protective equipment. We describe the use of NIV instruments with anti-viral filters and a non-vented mask, including a new NIV machine for COVID-19 respiratory care.

Although the references warn about the adverse effects of adding O2 without ventilatory assistance in patients with neuromuscular diseases (NMD), patients are still to be admitted to intensive care units with severe hypercapnia and CO2 narcosis. It seems that the problem is rediscovered as the years and generations go by. Unfortunately, many patients and their network of formal and informal caregivers are unaware of this risk, leading to significant worsening of symptoms, acute events, hospital admissions, and, in some cases, cause death. This article focuses on the dangers of O2 administration as well as its precise indications in people with NMD. The central problem is that the administration of O2 can remove the hypoxic impulse to ventilate, however, other mechanisms could be involved, but. The complete withdrawal of oxygen therapy is an even greater mistake if it is not supported by ventilatory assistance. It is possible to supply O2 and control CO2 safely. Oxygen should never be administered without constantly monitoring the CO2 level. Bi-level non-invasive ventilation (BiPAP) through a buccal, nasal interface or mouthpiece is the primary measure to reverse hypoventilation and achieve a decrease in PaCO2. The indications for oxygen therapy in people with NMD have been agreed upon and are reserved for specific situations. To improve the care of those with NMD and avoid iatrogenic interventions, education of the health team and support in the patient's environment is required.

Opioid-induced ventilatory impairment is the primary mechanism of harm from opioid use. Opioids suppress the activity of the central respiratory centres and are sedating, leading to impairment of alveolar ventilation.Respiratory physiological changes induced with acute opioid use include depression of the hypercapnic ventilatory response and hypoxic ventilatory response. In chronic opioid use a compensatory increase in hypoxic ventilatory response maintains ventilation and contributes to the onset of sleep-disordered breathing patterns of central sleep apnoea and ataxic breathing. Supplemental oxygen use in those at risk of opioid-induced ventilatory impairment requires careful consideration by the clinician to prevent failure to detect hypoventilation, if oximetry is being relied on, and the overriding of hypoxic ventilatory drive. Obstructive sleep apnoea and opioid-induced ventilatory impairment are frequently associated, with this interrelationship being complex and often unpredictable. Monitoring the patient for opioid-induced ventilatory impairment poses challenges in the areas of reliability, avoidance of alarm fatigue, cost, and personnel demands. Many situations remain in which patients cannot be provided effective analgesia without opioids, and for these the clinician requires a comprehensive knowledge of opioid-induced ventilatory impairment.

The effectiveness of bi-level positive airway pressure (BiPAP) in patients with acute hypercapnic respiratory failure (AHRF) due to etiologies other than chronic obstructive pulmonary disease (COPD) is unclear. To systematically review the evidence regarding the effectiveness of BiPAP in non-COPD patients with AHRF. The Cochrane Library, MEDLINE, EMBASE, and CINAHL Plus were searched according to prespecified criteria (PROSPERO-CRD42018089875). Randomized controlled trials (RCTs) assessing the effectiveness of BiPAP versus continuous positive airway pressure (CPAP), invasive mechanical ventilation, or O2 therapy in adults with non-COPD AHRF were included. The primary outcomes of interest were the rate of endotracheal intubation (ETI) and mortality. Risk-of-bias assessment was performed, and data were synthesized and meta-analyzed where appropriate. Two thousand four hundred and eighty-five records were identified after removing duplicates. Eighty-eight articles were identified for full-text assessment, of which 82 articles were excluded. Six studies, of generally low or uncertain risk-of-bias, were included involving 320 participants with acute cardiogenic pulmonary edema (ACPO) and solid tumors. No significant differences were seen between BiPAP ventilation and CPAP with regard to the rate of progression to ETI (risk ratio [RR] = 1.49, 95% confidence interval [CI], 0.63-3.62, P = 0.37) and in-hospital mortality rate (RR = 0.71, 95% CI, 0.25-1.99, P = 0.51) in patients with AHRF due to ACPO. The efficacy of BiPAP appears similar to CPAP in reducing the rates of ETI and mortality in patients with AHRF due to ACPO. Further research on other non-COPD conditions which commonly cause AHRF such as obesity hypoventilation syndrome is needed.

Congenital central hypoventilation syndrome (CCHS) is an uncommon genetic disease characterised by an autonomic nervous system dysfunction that affects ventilatory homeostasis. Involvement of other systems is also described, mainly cardiovascular, gastrointestinal and central nervous systems. We describe a rare case of CCHS diagnosed in a term newborn who presented with persistent apnoea in the first hours of life. After an exhaustive aetiological study excluding primary pulmonary, cardiac, metabolic and neurological diseases, this diagnosis was confirmed by a paired-like homeobox 2B gene sequence analysis. During hospitalisation, ventilation was optimised and multidisciplinary follow-up was initiated, including genetic counselling. At 2 months old, the child was discharged under non-invasive ventilation during sleep. This case illustrates the importance of early diagnosis, including genetic study and advances in home ventilation. These factors allow early hospital discharge and timely multidisciplinary intervention, which is crucial for patients' quality of life and outcome optimisation.