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Robba. Contemporary management of aneurysmal subarachnoid haemorrhage. An update for the intensivist. Intensive Care Med 2024;epublished April 10th

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• Published: 04 February 2020

Nutrition therapy in critical illness: a review of the literature for clinicians

• Kate J. Lambell   ORCID: orcid.org/0000-0002-4816-3023 1 , 2 , 3 ,
• Oana A. Tatucu-Babet 1 ,
• Lee-anne Chapple 4 , 5 ,
• Dashiell Gantner 1 , 6 &
• Emma J. Ridley 1 , 2  

Critical Care volume  24 , Article number:  35 ( 2020 ) Cite this article

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A Letter to this article was published on 19 June 2020

Nutrition therapy during critical illness has been a focus of recent research, with a rapid increase in publications accompanied by two updated international clinical guidelines. However, the translation of evidence into practice is challenging due to the continually evolving, often conflicting trial findings and guideline recommendations. This narrative review aims to provide a comprehensive synthesis and interpretation of the adult critical care nutrition literature, with a particular focus on continuing practice gaps and areas with new data, to assist clinicians in making practical, yet evidence-based decisions regarding nutrition management during the different stages of critical illness.

In recent years, there has been much interest in the role of nutrition therapy in critical illness with an increase in publications and two updated international clinical guidelines [ 1 , 2 ]. However, trial findings and guideline recommendations continue to be conflicting, making the translation of evidence into practice challenging. Further, it is becoming evident that the stage of critical illness and individual factors such as body composition may be important when considering how individuals might respond to nutrition interventions [ 3 , 4 ]. This narrative review aims to provide a summary and interpretation of the adult critical care nutrition literature, with a particular focus on continuing practice gaps and areas with new data, to help clinicians make practical, yet evidence-based decisions regarding nutrition management during critical illness.

The metabolic response to critical illness and the role of nutrition therapy

It is recognised that ‘one-size fits all’ and ‘set and forget’ approaches to nutrition do not adequately address the complex metabolic, hormonal, and immunological changes that occur with critical illness [ 3 , 5 ]. It is essential that clinicians understand these processes and the impact on nutrient metabolism [ 4 ]. In 1942, Cuthbertson described two distinct metabolic phases during acute illness—the ‘ebb’ or early shock phase, followed by the ‘flow’ or catabolic phase [ 6 ]. In brief, the ‘ebb’ phase is characterised by haemodynamic instability and hormonal changes (including insulin resistance) in order to prioritise the delivery of energy substrates to vital tissues [ 6 , 7 ]. This survival mechanism results in endogenous glucose production as well as lower energy expenditure compared to pre-injury [ 4 ]. The ‘flow’ phase involves the breakdown of tissue (including lean muscle tissue) in order to provide substrates to cover the immediate needs for the ‘fight or flight’ response and to reduce the risk of bleeding and infection [ 4 ]. More recently, a third, anabolic recovery phase has been described [ 3 ]. It is during this recovery phase when resynthesis of lost tissue can take place and the body may be more metabolically able to process delivered nutrients [ 3 , 4 ]. Currently, there is no known clinical marker to identify when an individual shifts from one phase of critical illness to another. For the purposes of this review which aims to provide practical recommendations, we have adapted the terminology from the 2019 European Society of Parenteral and Enteral Nutrition (ESPEN) critical care guideline to describe the different stages of critical illness: ICU day 1–2 (acute early phase), ICU day 3–7 (acute late phase), and after ICU day 7 (recovery phase) [ 2 ].

While it is considered that nutrition may be more physiologically available and hence more important in the later phase of illness, due to the average intensive care unit (ICU) length of stay (LOS), the majority of nutrition trials have provided nutrition interventions in the acute phases of illness (regardless of the intended trial intervention period). Traditionally, it was thought that aggressive nutrition in the early stages of critical illness may improve clinical outcomes. However, evidence from recent randomised controlled trials (RCTs) does not support this, finding no benefit or harm with early nutrition delivery [ 8 , 9 , 10 , 11 ]. An explanation for this may be because a substantial amount of energy was provided in a period of critical illness where energy expenditure is decreased and endogenous production is enhanced [ 4 ]. Specifically, harm was observed in The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically ill Patients (EPaNIC) trial, the largest nutrition trial in critical illness [ 10 ]. In a study of 4640 mixed ICU patients ( n  = 2818 (61%) cardiac surgery patients) who were eligible to receive EN, late initiation of PN (started on day 8 of the ICU stay) led to an increase in the proportion of patients discharged alive and earlier from ICU and hospital (hazard ratio (HR) 1.06; 95% CI 1.00–1.13; p  = 0.04 for both) when compared to PN commenced within 48 h of ICU admission [ 10 ]. Late initiation PN also led to a reduction in infectious complications (22.8% vs 26.2%, p  = 0.008), cholestasis, duration of mechanical ventilation (MV), duration of renal replacement therapy, and health care costs [ 10 ]. Most recently, results from the largest enteral nutrition (EN) trial, The Augmented versus Routine approach to Giving Energy Trial (TARGET), support the theory that augmented energy delivery in the early phase of illness does not improve clinical outcomes compared to standard care [ 8 ]. This pragmatic prospective RCT of 3957 patients assessed 90-day mortality with augmented energy delivery (based on a predictive estimate of 1 ml/kg ideal body weight for height per day), compared to routine care [ 8 ]. Energy delivery was 50% higher in the intervention group (~ 30 kcal/kg ideal body weight/day) over the median 6-day nutrition delivery period (and approximated clinician estimated energy aims) but did not impact mortality or any secondary clinical outcomes [ 8 ]. However, it must be noted this study included a very ‘general’ (or unselected) population and that overfeeding may have occurred. Further post hoc work may increase the understanding and clinical implications of these results. Lack of benefit has also been observed with hypocaloric (low energy and adequate protein) and trophic (low energy and protein) feeding strategies compared to standard care, also provided early in critical illness and for short periods [ 9 , 12 ]. The results of these trials support the hypothesis that for mixed ICU patients, nutrition interventions in the acute early and acute late phase of critical illness may not impact clinical outcomes and may cause harm in some groups. Therefore, less than 100% of energy expenditure should be targeted in this period due to endogenous glucose production. It remains unknown whether nutrition interventions continued for longer, impact functional recovery and quality of life [ 3 ].

Guidelines for nutrition therapy in critical illness

There are currently four international clinical practice guidelines available to inform the nutrition management of critically ill patients [ 1 , 2 , 13 , 14 ]. Table  1 summarises each guideline and outlines key recommendations and their level of supporting evidence.

Energy in critical illness

Determination of energy requirements is one of the most significant challenges in critical illness and is of vital importance as prescribed targets are used to guide nutrition delivery. Predictive equations that estimate energy expenditure are the most commonly used method due to their ease of application but are often inaccurate compared to measured energy expenditure using indirect calorimetry [ 15 ]. Table  2 summarises why predictive equation estimates vary from measured energy expenditure [ 16 , 17 ]. Importantly, inaccuracies increase at the extremes of weight, in the most severely unwell, and in older and more malnourished populations [ 16 , 18 ]. Despite these failings, predictive equations continue to be widely used and are recommended in international clinical guidelines in the absence of indirect calorimetry [ 1 , 2 ].

Estimating energy expenditure via VO 2 and VCO 2

Due to the persistent inaccuracies associated with the use of predictive equations, other methods (many of which have existed for some time) have been recently recommended in the 2019 ESPEN critical care guideline in the absence of indirect calorimetry [ 2 ]. Resting energy expenditure (REE) can be estimated via VCO 2 (carbon dioxide production) from the ventilator and the rewritten Weir formula (REE = VCO 2  × 8.19) or using VO 2 (oxygen consumption) from a pulmonary artery catheter via the Fick method [ 19 , 20 , 21 , 22 ]. A recent study in 84 critically ill patients reported a higher level of agreement between energy requirements estimated by the VCO 2 method and measured REE compared to other predictive equations [ 20 ]. There are methodological limitations to note with this method: an assumed normal respiratory quotient (RQ) of 0.85 is used, which is the RQ of most nutritional products (with RQ = VCO 2 /VO 2 , normally ranging between 0.67 and 1.2 depending on the proportion of carbohydrate, fat, and protein being combusted) [ 23 ]. However, in critical illness, RQ may also be influenced by endogenous glucose production and by periods of hypo- and hyper-ventilation, and is likely to fluctuate between populations [ 19 , 20 ].

Measuring energy expenditure in the critically ill—indirect calorimetry

Indirect calorimetry allows for the measurement of VO 2 and VCO 2 through the ventilator and is the gold standard method for measuring REE in critical illness when ideal test conditions are implemented [ 24 ]. Both the European (ESPEN) and American (ASPEN/SCCM) clinical practice guidelines recommend the use of indirect calorimetry to measure energy expenditure (Table  1 ) [ 1 , 2 ].

Despite the guideline recommendations, only three single-centre RCTs have investigated the impact of delivering energy according to a measured energy expenditure (via indirect calorimetry) compared to energy delivery using a 25-kcal/kg/day estimate (standard care) on clinical outcomes. The first, published in 2011, included 130 patients and observed a trend towards reduced hospital mortality (primary outcome) in the intervention group using intention to treat (ITT) analysis ( n  = 21/65, 32.3%, vs 31/65, 47.7%, p  = 0.058) [ 25 ]. However, infectious complications ( n  = 37 vs 20, p =  0.05) and mean (± standard deviation) duration of MV (16.1 ± 14.7 vs 10.5 ± 8.3 days, p  = 0.03) and ICU LOS (17.2 ± 14.6 vs 11.7 ± 8.4 days, p  = 0.04) were increased in the intervention group compared to standard care [ 25 ]. In a more recent and slightly larger trial of 203 patients, no differences were observed in the primary outcome (self-reported physical component summary score of SF-36 at 6 months) between intervention and control in the ITT analysis ( n  = 199, 22.9 vs 23.0, p  = 0.99, respectively) or in any clinically important secondary outcomes [ 11 ]. However, in a post hoc analysis, a longer median (interquartile range) ICU LOS was observed in the intervention group (8 (5–25) vs 7 (4–12) days, p  = 0.03) [ 11 ]. Lastly, in a pilot study ( n  = 40), no statistically significant differences were observed between groups in the primary outcome of change in bioelectrical impedance phase angle (related to nutritional status and prognosis) from baseline to ICU discharge [ 26 ]. However, a declining trend in mean phase angle was observed in the standard care group (3.31 ± 1.34° to 2.95 ± 1.15°, p  = 0.077), and a significantly shorter ICU LOS was reported in the intervention versus the standard care group (13 ± 8 vs 24 ± 20 days, p  < 0.05) [ 26 ].

Consistently across all three RCTs, indirect calorimetry was feasible and energy targets were more closely met when using indirect calorimetry in place of fixed-energy prescription. Methodological characteristics must be noted in interpreting these results; all studies were unblinded and single-centre in design and were likely underpowered to demonstrate true differences in clinical and functional recovery outcomes. Further, these studies aimed to meet 100% of indirect calorimetry targets early in the ICU admission, which recent evidence suggests is not beneficial, and there was limited investigation into high-risk subgroups in which indirect calorimetry may have avoided harm by under- or overfeeding (i.e. obesity). Despite this, these studies do not suggest that indirect calorimetry to guide energy delivery is superior to using predictive equations with regard to improving clinical outcomes.

Measurement or estimation of energy expenditure?

Regardless if energy expenditure is measured or estimated, there is no consensus on how much energy should be provided. Based on current evidence, the most significant benefit of using indirect calorimetry is to personalise energy prescription and avoid under- or overdelivery of energy across the different phases of critical illness. For this reason, it is the opinion of the authors that if indirect calorimetry is available, it should be used primarily in patients where the clinicians are concerned about under- or overestimating energy needs (i.e. obese and underweight individuals) [ 27 ]. When used, clinicians should aim for high-quality tests by reaching a steady test state (defined as a variation in VO 2 and VCO 2 less than 10% over five consecutive minutes), conduct tests for ≥ 30 min, and repeat tests at least weekly (or more frequently if clinically indicated) [ 24 ].

For the majority of clinicians, current practice will continue to include the use of a predictive equation for estimation of energy needs. Clinicians must be aware that accurate estimation of energy expenditure with a predictive equation requires considerable knowledge of the underlying patient condition, the factors that alter the metabolic response to illness, and the limitations of the equation being used. It is also important to consider that delivery of calories to meet measured or estimated energy expenditure may not equate to what should be provided to improve outcomes. This may be particularly relevant in the acute early phase of critical illness where endogenous substrate mobilisation provides a substantial portion of the energy requirement and insulin resistance occurs, and therefore, a conservative energy target should be the aim [ 28 ]. Energy prescription and energy delivery (including non-nutritional sources such as dextrose and propofol) should be regularly reviewed in the context of the patient’s clinical condition and metabolic phase to prevent considerable under- or overfeeding [ 29 ].

Protein in critical illness

In states of stress, such as in critical illness, the synthesis of acute phase proteins and those involved in immune function increase to support recovery [ 30 ]. Rapid and significant loss of skeletal muscle mass occurs to provide precursor amino acids to aid this process [ 31 ]. Despite a lack of definitive evidence, clinical guidelines recommend protein delivery of between 1.2 and 2 g/kg/day (Table  1 ) based on the assumption that like energy, delivery of adequate protein will attenuate skeletal muscle wasting and improve clinical outcomes. The ASPEN/SCCM guidelines also make recommendations for higher protein provision in specific clinical conditions (i.e. burns, obesity, and multi-trauma), which again are based on limited, primarily observational data and expert opinion [ 1 ]. The variation in the clinical guideline recommendations for protein delivery reflects the lack of good quality trials investigating the role of protein provision on clinical outcomes.

Protein delivery and clinical outcomes

Higher protein provision has been associated with improved survival in a number of observational studies [ 32 , 33 , 34 , 35 , 36 ]. Conversely, higher protein delivery during ICU admission has led to increased urea production and has been associated with increased muscle wasting in a small observational study [ 10 , 11 , 31 , 37 ].

In RCTs aiming to compare high versus lower protein delivery in critical illness, no benefit has been shown with an increased protein dose, although most have been underpowered to demonstrate an effect on clinical outcomes [ 11 , 37 , 38 , 39 ]. The largest RCT ( n  = 474) investigating intravenous protein provided at a dose of up to 100 g/day compared to standard care found no impact on the primary outcome of renal dysfunction [ 37 ]. A smaller RCT compared intravenous protein at a dose of either 0.8 g/kg ( n = 60) or 1.2 g/kg ( n = 59) delivered over ten days while controlling for energy intake [ 38 ]. While there was no difference in the primary outcome of handgrip strength, the group who received the higher protein dose had less fatigue and higher forearm thickness (using ultrasound) at day 7 [ 38 ]. However, these findings may be impacted by unadjusted confounders and must be interpreted with caution [ 40 ].

Timing of protein delivery may also influence clinical outcomes. Two observational studies have reported increased survival with early increased protein delivery (day 3–4) [ 32 , 33 ]. In the largest study ( n  = 2253), early protein delivery (> 0.7 g/kg/day versus ≤ 0.7 g/kg/day) was associated with increased survival (adjusted HR 0.83, 95% CI 0.71–0.97, p  = 0.017) [ 33 ]. Contrary to these findings, in a post hoc secondary analysis of the EPaNIC trial, a cumulative protein dose, rather than the cumulative glucose dose, early during ICU stay was associated with delayed ICU discharge [ 41 ]. Further, a single-centre retrospective cohort study ( n  = 455) reported a lower protein intake (< 0.8 g/kg/day) before day 3 and high protein intake (> 0.8 g/kg/day) after day 3 was associated with lower 6-month mortality (adjusted HR 0.609; 95% CI 0.480–0.772, p  < 0.001) compared to patients with overall high protein intake [ 42 ]. Prospective, randomised data is required to inform the most appropriate amount and timing of protein to deliver to critically ill patients. Adequately powered RCTs are urgently needed to better understand the impact of both protein dose and timing on clinical outcomes in critical illness. Such trials should ideally control for energy delivery, by ensuring it is consistent across both the intervention and control groups.

How much energy and protein do patients get in clinical practice?

One of the most important pieces of information that clinicians should consider is that patients do not receive the energy and protein dose that is prescribed. In a recent retrospective observational study of 17,524 patients, the mean ± standard deviation energy and protein received was 56 ± 30% and 52 ± 30% of the intended aim, respectively [ 43 ]. This has consistently been shown across different time periods and geographical regions [ 44 ]. The reasons for this are multifactorial, including interruptions to EN for procedures, delayed initiation of nutrition, and gastrointestinal intolerance [ 45 ].

What energy and protein targets should clinicians aim for?

In light of the current evidence, the authors support the gradual introduction of nutrition therapy during the acute phases of critical illness, with energy and protein targets outlined in Fig.  1 . In patients who are ‘at risk’ of refeeding syndrome, it is crucial that nutrition therapy is introduced slowly, and electrolytes are monitored closely and replaced as necessary [ 46 ]. If hypophosphatemia is present (e.g. < 0.65 mmol/l) in the first few days after starting nutrition therapy, then energy delivery should be restricted to ~ 50% requirements for 2–3 days [ 47 ].

Recommendations for nutritional management by nutritional status and phase of critical illness

• Enteral nutrition

When to start?

Early provision of EN (within 48 h of ICU admission) in patients who are mechanically ventilated is an established standard of care and supported by all clinical guidelines [ 1 , 2 , 13 , 14 ].

How should EN be delivered?

The most common method of delivering EN in ICU is via a gastric tube, with a continuous hourly infusion. However, this continuous supply of nutrients does not mimic normal volitional intake which is most commonly in the form of boluses followed by periods of fasting. Recently, it has been proposed that bolus (intermittent) feeding may be more physiologic and therefore superior to continuous feeding [ 48 ]. A systematic review was conducted as part of the recent ESPEN guidelines to investigate whether bolus EN has an advantage over continuously administered EN [ 2 ]. Including 5 small prospective studies and 236 patients, a significant reduction in diarrhoea was observed with continuous versus bolus administration of EN (RR 0.42, 95% CI 0.19–0.91, p  = 0.03) [ 2 ]. No differences in gastric residual volume, rates of aspiration, or pneumonia were observed. It has also been suggested that muscle protein synthesis may be improved when EN is delivered via a bolus when compared to continuous delivery, and a phase II multicentre RCT has recently completed recruitment to investigate this question ( ClinicalTrials.gov NCT02358512) [ 5 , 48 ]. Moving from continuous to bolus delivery of EN in the ICU is a significant change to practice in most countries, which would require a variation in feeding protocols and extensive education of clinical staff. Due to the considerable practice change associated, until definitive evidence is available to support one method of delivery over the other, it is reasonable that clinicians continue to deliver EN via a continuous infusion.

EN delivery—an ongoing challenge

International guidelines are unanimous in favouring EN delivery into the stomach or small bowel over parenteral nutrition (PN) [ 1 , 2 ]. Due to continued and consistent recommendations to meet energy requirements over many years, many strategies to ‘optimise’ EN delivery closer to predicted targets have been tested, including the use of evidence-based feeding protocols, small bowel feeding tubes, prokinetic drugs, and increase of the acceptable gastric residual volume [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. Guideline recommendations to maximise EN delivery are summarised in Table  3 . Despite the implementation of such interventions, these trials have observed modest to no increase in nutrition delivery and none have demonstrated a beneficial effect on clinical outcomes, potentially related to the disconnect between ‘delivery’ and ‘utilisation’ of nutrients.

• Parenteral nutrition

PN is indicated when the delivery of nutrients via the gastrointestinal tract is contraindicated or insufficient. PN can be provided either as a full source of nutrition (exclusive PN) or as an additional nutrition source when full requirements are not able to be met by oral intake or EN (supplemental PN). Recent RCT evidence has indicated there are no differences in clinical outcomes, including mortality and infective complications, when PN is provided versus EN in a modern day ICU setting and when energy provided is comparable in both groups [ 59 , 60 ]. Guideline recommendations for when to commence PN differ and are outlined in Table  1 . Due to the potential harm with early PN, it is the opinion of the authors that if oral intake or EN is contraindicated, then PN should only be considered between ICU days 3 and 7 and that supplemental PN be considered on an individual case-by-case basis (Fig.  1 ).

Body composition analysis

The measurement of weight and muscularity is important in the assessment of nutrition status and monitoring the effectiveness of nutrition interventions [ 61 ]. However, due to the extreme fluid shifts that critically ill patients experience, measured weight and/or muscularity assessed by traditional bedside methods (e.g., subjective physical assessment, mid-arm muscle circumference) may be inaccurate in this patient population [ 62 , 63 , 64 ]. Table  4 summarises the emerging tools for assessment of muscularity in the ICU setting: computed tomography image analysis, bioimpedance analysis, and ultrasound. Currently, these methods for assessing muscle mass and quality are mostly limited to research [ 64 , 65 , 66 ]. There is an essential need to evaluate which bedside tools can accurately measure muscle mass, and identify those individuals with lower than normal muscularity, as well as to better understand the clinical importance of changes in muscle health and the interface with nutrition interventions in critical illness.

Nutritional management in critically ill subgroups

RCTs conducted to date have focused on key practice questions, but included heterogenic populations. These studies have not shown clinical benefit with nutrition interventions for reasons previously discussed though there are several patient subgroups that may still benefit from nutrition interventions. In an attempt to investigate such groups, a number of large RCTs have included pre-planned subgroup analysis (e.g. response to the intervention according to differing BMI category). However, results from these types of analyses must be interpreted with caution as the sample size may be small. Moreover, if a benefit or harm is observed in a subgroup, but the overall trial result suggests no difference, it must be considered that another subgroup hidden in the heterogeneous population may have experienced the opposite effect.

Malnourished

The diagnosis of malnutrition in critically ill patients is challenging. Diagnostic tools, such as the widely used Subjective Global Assessment (SGA) and criteria outlined in the recent Global Leadership Initiative in Malnutrition (GLIM) recommendations, rely heavily on obtaining accurate anthropometrical data, weight and diet history, and the assessment of muscle mass, all of which are difficult to acquire in the acute early phase of ICU admission [ 61 ]. For this reason, RCT evidence attempting to investigate if patients who may be malnourished respond differently to nutrition is limited to subgroup analysis in patients with differing BMI categories or nutrition risk scores [ 10 , 12 , 67 ]. To date, no benefit has been observed when more or less nutrition is provided in these subgroups although the numbers included are often small. Further, BMI is a poor surrogate measure for malnutrition, and commonly used nutrition risk scores have not been well validated, which limits any conclusions on how nutrition therapy may affect outcomes in this vulnerable subgroup [ 2 ]. Despite the lack of evidence in this area, the authors support minimising progression of malnutrition. Where possible, clinicians should use local hospital guidelines or the recent GLIM criteria, combined with clinical judgement to diagnose malnutrition. As outlined in Fig.  1 , in severely malnourished patients, we encourage early low dose nutrition therapy in the acute early phase, with a slow progression to target during the acute late phase, while carefully monitoring for refeeding syndrome.

The unique and complex care needs of obese patients (BMI ≥ 30 kg/m 2 ) are amplified when they become critically ill and include a greater risk of insulin resistance and loss of lean muscle mass, and wide variations in macronutrient metabolism, which makes nutrition management complex [ 4 , 68 ]. There is currently very limited, low-quality evidence to inform nutrition provision in the critically ill obese patient, and as a result, the latest clinical guidelines provide inconsistent recommendations regarding energy and protein targets (Table 1 ).

In the TARGET trial, 1423 obese critically ill patients were included, representing the largest population of obese patients in an ICU nutrition study [ 8 ]. While not statistically significant, the obese subgroup was the only pre-specified subgroup where the point estimate sat on the side of benefit with greater energy delivery [ 8 ]. These results require formal evaluation in a robust, adequately powered and blinded clinical trial; however, they highlight that obese patients may respond differently to nutrition delivery than non-obese individuals and that there is a critical need for further research in this patient group.

In the absence of definitive evidence of the impact on functional recovery in particular, it is the opinion of the authors that obese patients should be managed like any other patient admitted to the ICU. If predictive equation estimates are used, a method to adjust body weight should be used in the nutrition prescriptions (not actual weight), and delivery monitored carefully with the knowledge that most predictive equations significantly underestimate requirements in this group [ 69 ]. It may be appropriate to consider a weight loss regime in the recovery phase once the acute illness has resolved.

The non-ventilated patient

Critically ill patients who are not intubated may have prolonged periods of inadequate oral intake. In a prospective observational study, 50 patients who were not receiving any EN or PN were studied for 7 days following endotracheal extubation [ 70 ]. The average daily energy and protein intake failed to exceed 50% of daily requirements on all 7 days for the entire population [ 70 ]. To prevent malnutrition, it is important that clinicians monitor the oral intake of awake patients and the authors support the ESPEN guideline recommendation that medical nutrition therapy should be considered for all patients staying in the ICU for > 2 days regardless of their ventilation status [ 2 ].

The limited data available indicates that the predominant mode of nutrition following an ICU admission is via the oral route and nutrition intake in this period remains below clinician recommendations. In 32 patients from 2 centres, nutrition intake was assessed 3 times per week in the post-ICU phase [ 71 ]. Oral nutrition was the most common type of nutrition therapy (55% of study days) [ 71 ]. The median [interquartile range] energy and protein intake was 79% [41–108%] and 73% [44–98%], respectively; however, considerable variation was observed depending on the type of nutrition therapy provided, with energy and protein provision the lowest in patients who received no additional oral nutrition supplements (37% [21–66%] of target energy and 48% [13–63%] protein) [ 71 ]. A second single-centre study of patients with traumatic brain injury indicated poorer intake post-ICU compared to in ICU, and nutritional deficit was significantly greater in patients who consumed oral nutrition alone compared to those receiving artificial nutrition support [ 72 ]. Despite this, dietitians spent just 20% of their time managing patients receiving oral nutrition therapy and saw the patients a mean of 2.2 (1.0) times per week for 34 (20) min per occasion on the post-ICU ward [ 72 ]. The predominant issues impacting nutrition intake are reported as appetite, disinterest in food, and taste changes [ 73 ].

Unfortunately, non-individualised, ‘one-size fits all’ processes to the management of nutrition are likely impacting on nutrition adequacy in the post-ICU period. In one of the only studies investigating processes that impact nutrition in the post-ICU period, it was found that of nine patients transferred to the post-ICU ward, six had their gastric tube removed on the advice of the medical team without assessment of nutrition intake [ 73 ]. Early removal of gastric tubes may improve patient comfort and is encouraged by many post-surgical protocols, but has the potential to negatively impact nutrition intake [ 73 ]. The decision to remove a tube should be made on a case-by-case basis and after consultation with the patient, the treating team, and the dietitian [ 74 ]. Among other possible causes, it is plausible that inadequate nutrition following critical illness may result in significant energy and protein deficit and may explain the lack of benefit in long-term outcomes observed in nutrition studies that have delivered an intervention in the acute early and late phases. This is an important knowledge gap for investigation and to provide initial insights; a multicentre RCT is underway ( ClinicalTrials.gov NCT03292237).

Results from recent large-scale trials highlight that in heterogeneous groups of patients, full feeding in the acute phases of critical illness does not provide an advantage over trophic feeding and may be harmful. It remains uncertain what impact specific nutrition interventions have in the recovery phase of illness and in specific subgroups who may respond differently to nutrition interventions. The effect of nutrition delivery on other clinically meaningful outcomes, such as muscle health and physical function, is also insufficiently studied. We recommend nutrition prescriptions that tailor for pre-admission nutrition status, and severity and stage of illness. Particular attention should be paid to patients that are in (or likely to stay in) ICU for greater than a week, with ongoing monitoring of nutrition delivery and regular review of measured or estimated nutrition requirements.

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Abbreviations

American Society of Parenteral and Enteral Nutrition/Society of Critical Care Medicine

European Society of Parenteral and Enteral Nutrition

Intensive care unit

Randomised control trial

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Lambell, K.J., Tatucu-Babet, O.A., Chapple, La. et al. Nutrition therapy in critical illness: a review of the literature for clinicians. Crit Care 24 , 35 (2020). https://doi.org/10.1186/s13054-020-2739-4

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Critical care nurses’ knowledge and attitudes and their perspectives toward promoting advance directives and end-of-life care

• Mu-Hsing Ho 1   na1 ,
• Hsiao-Chi Liu 2   na1 ,
• Jee Young Joo 3 ,
• Jung Jae Lee 1 &
• Megan F. Liu 4  

BMC Nursing volume  21 , Article number:  278 ( 2022 ) Cite this article

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End-of-life care can be a difficult and challenging process for critical care nurses in intensive care units (ICUs) due to the care plan shifts from providing life-sustaining measures to end-of-life care. The aims of this study were to assess critical care nurses' perceived knowledge and attitudes toward end-of-life care, as well as their perspectives on promoting advance directives and the associated factors.

A cross-sectional study was undertaken in an acute major metropolitan medical center in northern Taiwan between February and March 2020, and 250 critical care nurses were invited to participate in the study. Data on demographics, self-perceived knowledge of end-of-life care, attitudes toward end-of-life care, and perspectives of promoting advance directives were collected. A multiple linear regression model with stepwise selection was used to identify factors associated with their perspectives of promoting advance directives.

The law related to end-of-life care was rated as the least familiar part of the self-perceived end-of-life care knowledge, while ‘I have sufficient knowledge to care for patients who have accepted end-of-life care’ was the lowest level of agreement in attitude scores among critical care nurses. Increased levels of perceived knowledge ( β  = 0.134; p  = 0.045) and attitudes ( β  = 0.423; p  < 0.001) toward end-of-life care were associated with the perspectives of promoting advance directives. Nurses who worked in cardiac ( β  = -0.234; p  < 0.001) and respiratory ICUs ( β  = -0.135; p  = 0.024) had less motivation to promote advance directives ( F  = 16.943; p  < 0.001).

Given their important contributions to ICU care services, appropriate and meaningful support is required to optimize critical care nurses' involvement in end-of-life care. This study demonstrated a significant impact on perspectives of promoting advance directives of critical care nurse participants. Findings from this study can inform the design of effective nurse support programs to enhance the promotion of advance directives in intensive care settings.

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Introduction

In Taiwan, the Hospice Palliative Care Act was enacted into law in 2000, providing patients suffering from a terminal illness who were certified by two physicians the authority to sign advance directives and do not resuscitate (DNR) orders [ 1 ]. A directive can be made in one of two ways “ (1) it can be signed by a competent terminally ill patient or (2) it can be signed by a surrogate decision-maker, most commonly a close family member when a patient is unable to make such a decision for themselves due to dementia, delirium, or other types of cognitive impairment ” [ 1 ]. Advance directives are regarded as “a declaration, typically in writing, in which a person stated when mentally competent the type of health care he would desire to have at a future time when he is no longer capable [ 2 ].” Advance directives can assist healthcare personnel in respecting and following the preferred treatment of patients [ 3 ]. Before deciding on a DNR directive, the physician must consult with the patients and their family members. Initially, this used to exclusively apply to cancer patients in terminal condition, allowing them to receive hospice palliative treatment and make a DNR decision. Later modifications in 2009 increased insurance coverage of hospice and palliative care treatments to include non-malignant terminal conditions such as heart failure, chronic renal failure, liver cirrhosis and severe dementia. One of the most often used advance directives in end-of-life care is that when a person refuses to accept cardiopulmonary resuscitation (CPR) in the case of cardiac or respiratory arrest [ 1 ].

End-of-life care can be a difficult and challenging process in an intensive care unit (ICU) because many terminal illnesses involve withholding or withdrawing life-sustaining therapies, and in such situations, the role of critical care nurses shifts from providing life-sustaining measures to end-of-life care [ 4 , 5 ]. Critical care nurses face these terminal illnesses and provide direct care to critically ill patients in the ICU, and they are in the best position to promote advance directives and provide end-of-life care. However, a study in Taiwan discovered that critical care nurses have significantly lower knowledge of and attitudes toward advance directives than ICU physicians. Also, a disagreement about end-of-life decision-making between ICU physician and nurses was found regarding who initiated conversation about end-of-life care discussion [ 6 ]. Insufficient knowledge and low awareness of advance directives are likely to be the reasons that result in challenges for critical care nurses to provide end-of-life care in ICUs [ 7 ]. Given the importance of the involvement of critical care nurses in end-of-life care such as decision-making and promoting advance directives, more strategies for practice development to prepare and support nurses in providing end-of-life care in intensive care settings are needed [ 6 , 8 ]. Understanding the perceived knowledge of and attitudes toward end-of-life care can inform further development of strategies to support nurses in providing end-of-life care and promoting advance directives. Thus, this study aimed to assess (1) critical care nurses' self-perceived end-of-life care knowledge and attitudes toward terminal patients, as well as their perspectives of promoting advance directives; and (2) the factors associated with critical care nurses’ perspectives of promoting advance directives.

Research design and setting

A cross-sectional survey was conducted among critical care nurses between February and March 2020. The research site was a major acute-care metropolitan medical center with approximately 120 ICU beds located in northern Taiwan.

Participants

Critical care nurses who met the selection criteria were invited to participate in this study. The inclusion criteria were a status as a registered nurse working in an ICU and agreed to participate in this study. Nurses who were receiving a temporary ICU training in the ICU were excluded. Critical care nurses who worked in a pediatric or neonatal ICU or the emergency room were also excluded, given the nature of nursing practice and workload, admitted patients, and the equipment/medications used in between adult ICU, pediatric or neonatal ICU, and the emergency room were different in Taiwan. G* power vers. 3.0.10 software was used to estimate the sample size [ 9 ]. The statistical test and model settings for the sample size estimation were as follow: F test as the test family; linear multiple regression: fixed model; R 2 deviation from zero as the statistical test with a prior power analysis (given α , power, and effect size); and parameter settings ( α  = 0.05, 1– β  = 0.95. f 2 effect size = 0.08, and number of predictors = 3). Parameter settings were established according to a previous study on perspectives of promoting advance directives as an outcome [ 10 ]. An estimated sample size of 219 participants was considered sufficient.

Ethical approval

The study protocol was reviewed and approved by the Hospital Institutional Review Board of the research site. Ethical approval was granted with approval no.: 108152-F. Written consent was obtained prior to the commencement of data collection. Subjects who were invited to participate could choose to discontinue their participation at any time.

Data collection

A survey was developed based on a literature review and expert input. The tool was comprised of four parts that had to be completed, namely demographics, self-perceived knowledge of end-of-life care, attitudes toward end-of-life care, and perspectives of promoting advance directives. The survey was distributed by a research assistant to potential participants in person who agreed to join the study.

Demographic characteristics

Information of critical care nurses we collected included gender, age, educational level, years working as an ICU nurse, type of their workplace ICU, and continuing education in end-of-life care per year (hours).

Self-perceived end-of-life care knowledge of terminal patients

In total, 23 questions and a five-point Likert scale were used. Positively keyed questions were assigned 5 as “very familiar”, 4 as “familiar”, 3 as “neither familiar nor unfamiliar”, 2 as “unfamiliar”, or 1 as “very unfamiliar”. The higher the score, the higher the degree of self-perceived end-of-life care knowledge of critical care nurses, and the higher the tendency that critical care nurses would provide end-of-life care. This scale was developed to examine self-perceived end-of-life care knowledge towards terminal patients among critical care nurses. The content validity and the internal consistency (Cronbach’s alpha = 0.94) were established [ 11 ].

End-of-life care attitudes towards terminal patients

In total, 17 questions and a five-point Likert scale were adopted, with 5 as “extremely agree”, 4 as “agree”, 3 as “neither agree nor disagree”, 2 as “disagree”, or 1 as “extremely disagree”. The higher the score, the more positive care attitudes towards terminal patients from critical care nurses, and the higher the tendency that the critical care nurses would provide end-of-life care. This scale aimed to assess end-of-life care attitudes among critical care nurses towards terminal patients. The content validity and the internal consistency (Cronbach’s alpha = 0.85) were confirmed [ 11 ].

Perspectives of promoting advance directives

Perspectives of promoting advance directives scale were adopted from Hsieh et al. (2010) who developed a test for Taiwanese nursing staff. In total, 24 questions with a five-point Likert scale were used, with 1 as “extremely disagree”, 2 as “disagree”, 3 as “neither agree nor disagree”, 4 as “agree”, and 5 as “extremely agree”. Negatively keyed questions were inversely scored when summary scores were computed. The total score of the questionnaire ranged 24 ~ 120 points. The higher the score, the more-positive attitudes nursing staff had towards promoting advance directives. A lower score indicated that there would be challenges or negative attitudes towards discussing advance directives between nursing staff and patients. The content validity and internal consistency (Cronbach’s alpha = 0.80) were confirmed [ 10 ].

Data analysis

All data were entered into SPSS© vers. 25.0 for analysis (IBM SPSS Statistics for Windows, vers. 25.0. IBM, Armonk, NY, USA). Descriptive analyses, including the mean, standard deviation (SD), and frequency distributions were used to summarize data relating to demographics, self-perceived knowledge of end-of-life care, attitudes toward end-of-life care, and perspectives of promoting advance directives. Multiple imputation was employed to handle missing values. A multiple linear regression model with stepwise selection was used to identify factors associated with perspectives of promoting advance directives. All variables including demographics were entered in the regression model, and significant variables were selected and included in the final model. The variance inflation factor (VIF) was also examined to discover potential multicollinearity issues between variables. Statistical significance for all tests was set to p  < 0.05.

In total, 250 responses were received. Of these, 88.4% ( n  = 220) of subjects were female, and 76.0% ( n  = 341) were aged 20 ~ 30 years (Table 1 ). Ninety-two percent ( n  = 231) of participants had an undergraduate education level, and more than half ( n  = 148; 59.2%) had been an ICU nurse for 1 ~ 5 years. Most ( n  = 76; 30.4%) participants worked in a medical ICU, followed by surgical ICUs ( n  = 57; 22.8%) and cardiac ICUs ( n  = 54; 21.6%). Almost all participants ( n  = 244; 98.0%) received ≤ 5 h of continuing education in end-of-life care per year.

Self-perceived end-of-life care knowledge of and attitudes towards terminal patients

Critical care nurses reported that ‘I am familiar with the importance of collaboration among end-of-life care team members’ (mean = 4.17; SD = 0.54), ‘I am familiar with the purpose of end-of-life care’ (mean = 4.12; SD = 0.51), and ‘I am familiar with the role and function of an end-of-life care team member’ (mean = 4.12; SD = 0.53) were the most familiar self-perceived aspects of end-of-life care knowledge towards terminal patients, demonstrating higher degree of self-perceived end-of-life care knowledge than other items. The least familiar part of the self-perceived end-of-life care knowledge with the lowest score was ‘I am familiar with the laws relating to end-of-life care’ (mean = 3.42; SD = 0.92), showing that the nurses had lower degree of self-perceived end-of-life care knowledge regarding the laws relating to end-of life care (Table 2 ). As for the end-of-life care attitudes of critical care nurses towards terminal patients, ‘I believe that providing end-of-life care information to patients and their family is beneficial’ (mean = 4.40; SD = 0.57), ‘I will agree to disconnect the ventilator under legal conditions for a terminal patient’ (mean = 4.38; SD = 0.58), and ‘I believe that high-quality end-of-life care can reduce medical disputes’ (mean = 4.34; SD = 0.62) were the most familiar items, while ‘I have sufficient knowledge to care for patients who have accepted end-of-life care’ was the item with the lowest level of agreement in attitude scores (Table 3 ).

Critical care nurses’ perspectives of promoting advance directives

Figure  1 shows that statements with higher agreement of perspectives of promoting advance directives were ‘Discussing advance directives with patients improves the quality of their end-of-life’ (mean = 4.32; SD = 0.53), ‘Discussing advance directives with patients respects patients’ values’ (mean = 4.31; SD = 0.52), and ‘Discussing advance directives with patients allows for a better understanding of patients’ expectations of their treatment plans (mean = 4.26; SD = 0.54)’, and the statement with the lowest agreement was ‘I am worried that discussing advance directives with patients may cause annoyance or discomfort’ (mean = 2.56; SD = 1.01).

Statements of perspectives of promoting advance directives among critical care nurses. Note . Ordered by mean values, the higher the score, the more-positive attitude critical care nurses had towards promoting advance directives. A lower score (1 or 2) indicates that there would be challenges or negative attitudes towards discussing advance directives between critical care nurses and patients

Factors associated with perspectives of promoting advance directives

The stepwise multiple regression analysis revealed that critical care nurses self-perceived end-of-life care knowledge ( β  = 0.134; p  = 0.045) and attitudes ( β  = 0.423; p  < 0.001) towards terminal patients were factors associated with perspectives of promoting advance directives. Nurses with higher self-perceived end-of-life care knowledge and more-positive end-of-life care attitudes had higher motivation to promote advance directives. Also, compared to nurses who worked in medical ICUs, those who worked in cardiac ( β  = -0.234; p  < 0.001) and respiratory ( β  = -0.135; p  = 0.024) ICUs had lower motivation to promote advance directives ( F  = 16.943; p  < 0.001). All VIFs were < 10 which showed that no multicollinearity issue existed in the regression model (Table 4 ).

This study assessed critical care nurses' self-perceived knowledge of and attitudes toward end-of-life care, as well as their perspectives of promoting advance directives. Critical care nurses demonstrated high perceived knowledge of end-of-life care on items about the purpose of end-of-life care, the role and function of end-of-life care team members, and the importance of collaboration among end-of-life care team members. This shows that critical care nurses are equipped with fundamental knowledge of end-of-life care and understand that teamwork with other healthcare professionals in the end-of-life care team is important. Other research suggested that interprofessional interventions and interdisciplinary teamwork have the potential to support ICU staff to provide better end-of-life care [ 12 , 13 , 14 ]. The least familiar item among critical care nurses was about laws relating to end-of-life care, which referred to the Hospice Palliative Care Act in Taiwan [ 1 ]. Future studies, interventions, and continuing education can consider putting more efforts in enhancing critical care nurses’ understanding of end-of-life care law.

In line with previous studies that attitudes toward end-of-life in critical care nurses are positive [ 6 , 7 , 11 ], both self-perceived knowledge of and attitudes toward end-of-life care were found to be significant factors of perspectives of promoting advance directives, and future studies can be informed by our findings to develop tailor-made interventions for getting critical care nurses involved and engaged in end-of-life care and decision-making processes [ 15 ]. The role of critical care nurses being actively involved in end-of-life care and discussions has been highlighted, and they are essential partners in the end-of-life decision-making process within the end-of-life care team [ 16 ]. Increasing nurses’ knowledge and confidence to provide input in end-of-life discussions needs more research attention [ 17 , 18 ].

Our findings also revealed that critical care nurses realized that discussing advance directives with patients improved their quality of end-of-life, respected their values, and allowed for a better understanding of patients’ expectations of their treatment plans. In addition, critical care nurses were not worried that discussing advance directives with patients might cause annoyance or discomfort. This is dissimilar to a previous study that assessed perspectives of promoting advance directives among nurses working in a hemodialysis room, in which more than 65% of those nurses were worried that discussing advance directives with patients might cause annoyance or discomfort [ 10 ]. A possible reason might be that as critical care nurses are frontline care providers who care for critically ill patients, they understand that advance directives would be one of the options to provide better end-of-life care and they have to face many patients with terminal illnesses and dying patients [ 19 , 20 ]. Also, we identified that compared to nurses who work in medical ICUs, those who work in cardiac and respiratory ICUs have lower motivation to promote advance directives. This is likely because mortality rates in and the severity of diseases are higher in medical ICUs in Taiwan. We suggest adding advance directives-relevant information on laws into the content of continuing education for end-of-life care, particularly for cardiac and respiratory ICU nurses. Educational strategies such as simulated education with role-playing scenarios to introduce advance directives to patients would likely be effective in improving nurses’ end-of-life care [ 21 , 22 ]. Furthermore, the dignity of patients with palliative needs were also needed to be considered when developing the aforementioned educational strategies for nurses to promote palliative care. As a comprehensive integrated review has summarized a model of dignity that identifying several themes such as family care and support, social justice, reliable health care, which are highly relevant to be embedded in providing nursing care [ 23 ].

Study limitations

The main limitation of this study to be acknowledged is that the survey was only distributed to participants in a major acute-care metropolitan medical center located in northern Taiwan. The nonprobability sampling method used in this study to choose the hospital may influence the external validity of the study, and therefore, the results may not be generalizable to other areas in Taiwan due to representative bias. Future research should enroll more participants that particularly reflect different areas to conduct a multicenter study to compare the results. Nevertheless, this study discovered critical care nurses' perceived knowledge and attitudes toward end-of-life care, as well as their perspectives on promoting advance directives and the associated factors using validated instruments. Findings from this study can inform the design of effective nurse support programs to enhance the promotion of advance directives in intensive care settings.

Conclusions

Self-perceived knowledge and attitudes toward end-of-life care, and perspectives of promoting advance directives of critical care nurses were assessed. We found that increased levels of perceived knowledge and attitudes toward end-of-life care were associated with the perspectives of promoting advance directives. Nurses who worked in cardiac and respiratory ICUs had less motivation to promote advance directives. This study demonstrated a significant impact of perspectives of promoting advance directives of critical care nurse participants. Given their important contribution to ICU care services, appropriate and meaningful support is required to optimize critical care nurses' involvement in end-of-life care.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank the critical care nurses who so generously participated in the survey.

Author information

Mu-Hsing Ho and Hsiao-Chi Liu contributed equally to this work.

Authors and Affiliations

School of Nursing, LKS Faculty of Medicine, The University of Hong Kong, 5/F, Academic Building 3 Sassoon Road, Pokfulam, Hong Kong, Hong Kong

Mu-Hsing Ho & Jung Jae Lee

Department of Nursing, Far Eastern Memorial Hospital, 21 Nanya S. Rd., Sec. 2, Banciao Dist., New Taipei City, 220, Taiwan

Hsiao-Chi Liu

College of Nursing, Gachon University, 191 Hambakmoero, Yeonsu-gu, Incheon, Korea

Jee Young Joo

School of Gerontology and Long-Term Care, College of Nursing, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan

Megan F. Liu

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Contributions

MHH: design of the work, the acquisition, analysis, interpretation of data, have drafted the work; HCL: analysis, interpretation of data; JYJ: design of the work, interpretation of data; JJL: analysis, interpretation of data, have drafted the work; MFL: design of the work, analysis, interpretation of data, have drafted the work. The author(s) read and approved the final manuscript.

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Correspondence to Megan F. Liu .

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The study protocol was reviewed and approved by the Far Eastern Memorial Hospital Research Ethics Review Committee in Taiwan for ethical considerations (approval number: 108152-F). All methods were carried out in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants. Legally Authorized Representatives of illiterate participants provided informed consent for the study.

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Ho, MH., Liu, HC., Joo, J.Y. et al. Critical care nurses’ knowledge and attitudes and their perspectives toward promoting advance directives and end-of-life care. BMC Nurs 21 , 278 (2022). https://doi.org/10.1186/s12912-022-01066-y

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Burnout in critical care nurses: a literature review

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• PMID: 23342935

Burnout and its development in critical care nurses is a concept that has received extensive study, yet remains a problem in Canada and around the world. Critical care nurses are particularly vulnerable to developing burnout due to the chronic occupational stressors they are exposed to, including high patient acuity, high levels of responsibility, working with advanced technology, caring for families in crisis, and involved in morally distressing situations, particularly prolonging life unnecessarily. The purpose of this article is to explore how the chronic stressors that critical care nurses are exposed to contribute to the development of burnout, and strategies for burnout prevention. A review of the literature between the years 2007 and 2012 was conducted and included the search terms burnout, moral distress, compassion fatigue, intensive care, critical care, and nursing. The search was limited to the adult population, English language, and Western cultures. The results revealed that nurse managers play a crucial role in preventing burnout by creating a supportive work environment for critical care nurses. Strategies for nurse managers to accomplish this include being accessible to critical care nurses, fostering collegial relationships among the different disciplines, and making a counsellor or grief team available to facilitate debriefing after stressful situations, such as a death. In addition, critical care nurses can help prevent burnout by being a support system for each other and implementing self-care strategies.

Publication types

• Burnout, Professional / prevention & control*
• Burnout, Professional / psychology*
• Critical Care*
• Nurses / psychology*
• Risk Factors
• Social Support
• Stress, Psychological / prevention & control
• Stress, Psychological / psychology

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Expert Analysis Reveals Critical Insights for Optimizing Care in LA-NSCLC

Authors conducted a systematic literature review to gather evidence on the appropriateness of recommended treatments for locally advanced non–small cell lung cancer (LA-NSCLC) from the American Radium Society Appropriate Use Criteria Thoracic Committee.

An expert analysis has concluded that evidence-based guidance from the American Radium Society Appropriate Use Criteria (ARS AUC) Thoracic Committee on several treatment modalities for locally advanced non–small cell lung cancer (LA-NSCLC)—which accounts for 20% to 30% of lung cancer cases at diagnosis—does have utility for optimizing multidisciplinary care in this challenging patient population.

Findings were published online today in JAMA Oncology , with the study investigators noting the need for their review stems from the most recent appropriate use criteria for these patients came out in 2014 and the publication since then of studies examining radiation therapy technique and dosing, and systemic therapy selection. Their systematic literature review involved relevant articles from PubMed—69 references comprising 30 well-designed studies, 9 moderately well-designed studies, 2 studies with design limitations, and 28 nonprimary data references—that were published between January 1966 and December 2022 and focused on combined chemoradiation therapy, dose escalation, consolidation systemic therapy, and palliative radiotherapy.

“Information regarding the treatment of recurrent disease either locally or with oligometastatic disease after primary treatment for LA-NSCLC is increasingly available and should be integrated into modern clinical decision-making,” they wrote. “Additionally, the use of molecular markers such as EGFR, ALK, and PD-L1 has significantly informed systemic therapy options for many patients with NSCLC, and their integration into LA-NSCLC treatment pathways needs to be clarified.”

Study authors also highlight the importance of multidisciplinary input and shared decision-making with patients who have LA-NSCLC during treatment discussions Image credit: | Image Credit: didesign - stock.adobe.com

This consensus-based document encompasses key practice paradigms and 6 typical clinical scenarios in patients with unresectable disease, which covers most patients who have LA-NSCLC, the authors noted:

• Treatment of a patient with unresectable LA-NSCLC and good performance status
• Treatment of a patient with unresectable LA-NSCLC and good performance status and bulky disease
• Treatment of a patient with EGFR-positive unresectable LA-NSCLC and good performance status
• Treatment of a symptomatic patient with unresectable LA-NSCLC and poor performance status
• Treatment of an asymptomatic patient with unresectable LA-NSCLC and poor performance status
• Treatment of a patient with unresectable LA-NSCLC and local recurrence

The ARS AUC Thoracic Committee, citing a lack of uniform guidance, delivers 3 summary recommendations from their review:

• For unresectable patients who have LA-NSCLC, appropriate standard-of-care disease management should encompass combined concurrent radical (60-70 Gy) platinum-based chemoradiation and consolidation therapy with durvalumab per PD-L1/ EGFR status.
• Intensity-modulated radiotherapy, because it is conformal in delivery and widely available, should be used when clinicians are planning how to best deliver radiotherapy regimens; tumor bulk and treatment availability, however, may necessitate a switch to 3-dimensional conformal radiotherapy or intensity-modulated proton therapy.
• In patient cases with either poor performance status and/or pulmonary status, potential for treatment-related toxicity should be a primary consideration, with the authors citing the variety of available palliative and radical fractionation schedules and the benefits of either sequential therapy or radiation therapy alone vs concurrent regimens.

“Treatment appropriateness of a variety of LA-NSCLC scenarios was assessed by a consensus-based modified Delphi approach using a range of 3 points to 9 points to denote consensus agreement,” the authors explained regarding how they arrived at their recommendations.

The authors also highlight the importance of multidisciplinary input and shared decision-making with patients who have LA-NSCLC during treatment discussions, concluding that “various surgical, radiotherapeutic, and systemic options are available to manage this challenging patient population.”

Rodrigues G, Higgins KA, Rimner A, et al. American Radium Society appropriate use criteria for unresectable locally advanced non–small cell lung cancer. JAMA Oncol . Published online April 11, 2024. doi:10.1001/jamaoncol.2024.0294

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The potential for artificial intelligence to transform healthcare: perspectives from international health leaders

• Christina Silcox 1 ,
• Eyal Zimlichmann 2 , 3 ,
• Katie Huber   ORCID: orcid.org/0000-0003-2519-8714 1 ,
• Neil Rowen 1 ,
• Robert Saunders 1 ,
• Mark McClellan 1 ,
• Charles N. Kahn III 3 , 4 ,
• Claudia A. Salzberg 3 &
• David W. Bates   ORCID: orcid.org/0000-0001-6268-1540 5 , 6 , 7  

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• Health policy
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Artificial intelligence (AI) has the potential to transform care delivery by improving health outcomes, patient safety, and the affordability and accessibility of high-quality care. AI will be critical to building an infrastructure capable of caring for an increasingly aging population, utilizing an ever-increasing knowledge of disease and options for precision treatments, and combatting workforce shortages and burnout of medical professionals. However, we are not currently on track to create this future. This is in part because the health data needed to train, test, use, and surveil these tools are generally neither standardized nor accessible. There is also universal concern about the ability to monitor health AI tools for changes in performance as they are implemented in new places, used with diverse populations, and over time as health data may change. The Future of Health (FOH), an international community of senior health care leaders, collaborated with the Duke-Margolis Institute for Health Policy to conduct a literature review, expert convening, and consensus-building exercise around this topic. This commentary summarizes the four priority action areas and recommendations for health care organizations and policymakers across the globe that FOH members identified as important for fully realizing AI’s potential in health care: improving data quality to power AI, building infrastructure to encourage efficient and trustworthy development and evaluations, sharing data for better AI, and providing incentives to accelerate the progress and impact of AI.

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Introduction

Artificial intelligence (AI), supported by timely and accurate data and evidence, has the potential to transform health care delivery by improving health outcomes, patient safety, and the affordability and accessibility of high-quality care 1 , 2 . AI integration is critical to building an infrastructure capable of caring for an increasingly aging population, utilizing an ever-increasing knowledge of disease and options for precision treatments, and combatting workforce shortages and burnout of medical professionals. However, we are not currently on track to create this future. This is in part because the health data needed to train, test, use, and surveil these tools are generally neither standardized nor accessible. This is true across the international community, although there is variable progress within individual countries. There is also universal concern about monitoring health AI tools for changes in performance as they are implemented in new places, used with diverse populations, and over time as health data may change.

The Future of Health (FOH) is an international community of senior health care leaders representing health systems, health policy, health care technology, venture funding, insurance, and risk management. FOH collaborated with the Duke-Margolis Institute for Health Policy to conduct a literature review, expert convening, and consensus-building exercise. In total, 46 senior health care leaders were engaged in this work, from eleven countries in Europe, North America, Africa, Asia, and Australia. This commentary summarizes the four priority action areas and recommendations for health care organizations and policymakers that FOH members identified as important for fully realizing AI’s potential in health care: improving data quality to power AI, building infrastructure to encourage efficient and trustworthy development and evaluations, sharing data for better AI, and providing incentives to accelerate the progress and impact of AI.

Powering AI through high-quality data

“Going forward, data are going to be the most valuable commodity in health care. Organizations need robust plans about how to mobilize and use their data.”

AI algorithms will only perform as well as the accuracy and completeness of key underlying data, and data quality is dependent on actions and workflows that encourage trust.

To begin to improve data quality, FOH members agreed that an initial priority is identifying and assuring reliable availability of high-priority data elements for promising AI applications: those with the most predictive value, those of the highest value to patients, and those most important for analyses of performance, including subgroup analyses to detect bias.

Leaders should also advocate for aligned policy incentives to improve the availability and reliability of these priority data elements. There are several examples of efforts across the world to identify and standardize high-priority data elements for AI applications and beyond, such as the multinational project STANDING Together, which is developing standards to improve the quality and representativeness of data used to build and test AI tools 3 .

Policy incentives that would further encourage high-quality data collection include (1) aligned payment incentives for measures of health care quality and safety, and ensuring the reliability of the underlying data, and (2) quality measures and performance standards focused on the reliability, completeness, and timeliness of collection and sharing of high-priority data itself.

Trust and verify

“Your AI algorithms are only going to be as good as the data and the real-world evidence used to validate them, and the data are only going to be as good as the trust and privacy and supporting policies.”

FOH members stressed the importance of showing that AI tools are both effective and safe within their specific patient populations.

This is a particular challenge with AI tools, whose performance can differ dramatically across sites and over time, as health data patterns and population characteristics vary. For example, several studies of the Epic Sepsis Model found both location-based differences in performance and degradation in performance over time due to data drift 4 , 5 . However, real-world evaluations are often much more difficult for algorithms that are used for longer-term predictions, or to avert long-term complications from occurring, particularly in the absence of connected, longitudinal data infrastructure. As such, health systems must prioritize implementing data standards and data infrastructure that can facilitate the retraining or tuning of algorithms, test for local performance and bias, and ensure scalability across the organization and longer-term applications 6 .

There are efforts to help leaders and health systems develop consensus-based evaluation techniques and infrastructure for AI tools, including HealthAI: The Global Agency for Responsible AI in Health, which aims to build and certify validation mechanisms for nations and regions to adopt; and the Coalition for Health AI (CHAI), which recently announced plans to build a US-wide health AI assurance labs network 7 , 8 . These efforts, if successful, will assist manufacturers and health systems in complying with new laws, rules, and regulations being proposed and released that seek to ensure AI tools are trustworthy, such as the EU AI Act and the 2023 US Executive Order on AI.

Sharing data for better AI

“Underlying these challenges is the investment required to standardize business processes so that you actually get data that’s usable between institutions and even within an institution.”

While high-quality internal data may enable some types of AI-tool development and testing, this is insufficient to power and evaluate all AI applications. To build truly effective AI-enabled predictive software for clinical care and predictive supports, data often need to be interoperable across health systems to build a diverse picture of patients’ health across geographies, and reliably shared.

FOH members recommended that health care leaders work with researchers and policymakers to connect detailed encounter data with longitudinal outcomes, and pilot opportunities across diverse populations and systems to help assure valid outcome evaluations as well as address potential confounding and population subgroup differences—the ability to aggregate data is a clear rate-limiting step. The South African National Digital Health Strategy outlined interventions to improve the adoption of digital technologies while complying with the 2013 Protection of Personal Information Act 9 . Although challenges remain, the country has made progress on multiple fronts, including building out a Health Patient Registration System as a first step towards a portable, longitudinal patient record system and releasing a Health Normative Standards Framework to improve data flow across institutional and geographic boundaries 10 .

Leaders should adopt policies in their organizations, and encourage adoption in their province and country, that simplify data governance and sharing while providing appropriate privacy protections – including building foundations of trust with patients and the public as previously discussed. Privacy-preserving innovations include ways to “share” data without movement from protected systems using approaches like federated analyses, data sandboxes, or synthetic data. In addition to exploring privacy-preserving approaches to data sharing, countries and health systems may need to consider broad and dynamic approaches to consent 11 , 12 . As we look to a future where a patient may have thousands of algorithms churning away at their data, efforts to improve data quality and sharing should include enabling patients’ access to and engagement with their own data to encourage them to actively partner in their health and provide transparency on how their data are being used to improve health care. For example, the Understanding Patient Data program in the United Kingdom produces research and resources to explain how the National Health Service uses patients’ data 13 . Community engagement efforts can further assist with these efforts by building trust and expanding understanding.

FOH members also stressed the importance of timely data access. Health systems should work together to establish re-usable governance and privacy frameworks that allow stakeholders to clearly understand what data will be shared and how it will be protected to reduce the time needed for data use agreements. Trusted third-party data coordinating centers could also be used to set up “precertification” systems around data quality, testing, and cybersecurity to support health organizations with appropriate data stewardship to form partnerships and access data rapidly.

Incentivizing progress for AI impact

“Unless it’s tied to some kind of compensation to the organization, the drive to help implement those tools and overcome that risk aversion is going to be very high… I do think that business driver needs to be there.”

AI tools and data quality initiatives have not moved as quickly in health care due to the lack of direct payment, and often, misalignment of financial incentives and supports for high-quality data collection and predictive analytics. This affects both the ability to purchase and safely implement commercial AI products as well as the development of “homegrown” AI tools.

FOH members recommended that leaders should advocate for paying for value in health – quality, safety, better health, and lower costs for patients. This better aligns the financial incentives for accelerating the development, evaluation, and adoption of AI as well as other tools designed to either keep patients healthy or quickly diagnose and treat them with the most effective therapies when they do become ill. Effective personalized health care requires high-quality, standardized, interoperable datasets from diverse sources 14 . Within value-based payments themselves, data are critical to measuring quality of care and patient outcomes, adjusted or contextualized for factors outside of clinical control. Value-based payments therefore align incentives for (1) high-quality data collection and trusted use, (2) building effective AI tools, and (3) ensuring that those tools are improving patient outcomes and/or health system operations.

Data have become the most valuable commodity in health care, but questions remain about whether there will be an AI “revolution” or “evolution” in health care delivery. Early AI applications in certain clinical areas have been promising, but more advanced AI tools will require higher quality, real-world data that is interoperable and secure. The steps health care organization leaders and policymakers take in the coming years, starting with short-term opportunities to develop meaningful AI applications that achieve measurable improvements in outcomes and costs, will be critical in enabling this future that can improve health outcomes, safety, affordability, and equity.

Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Acknowledgements

The authors acknowledge Oranit Ido and Jonathan Gonzalez-Smith for their contributions to this work. This study was funded by The Future of Health, LLC. The Future of Health, LLC, was involved in all stages of this research, including study design, data collection, analysis and interpretation of data, and the preparation of this manuscript.

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Christina Silcox, Katie Huber, Neil Rowen, Robert Saunders & Mark McClellan

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Eyal Zimlichmann

Future of Health, Washington, DC, USA

Eyal Zimlichmann, Charles N. Kahn III & Claudia A. Salzberg

Federation of American Hospitals, Washington, DC, USA

Charles N. Kahn III

Division of General Internal Medicine, Brigham and Women’s Hospital, Boston, MA, USA

David W. Bates

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C.S., K.H., N.R., and R.S. conducted initial background research and analyzed qualitative data from stakeholders. All authors (C.S., E.Z., K.H., N.R., R.S., M.M., C.K., C.A.S., and D.B.) assisted with conceptualization of the project and strategic guidance. C.S., K.H., and N.R. wrote initial drafts of the manuscript. All authors contributed to critical revisions of the manuscript and read and approved the final manuscript.

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Correspondence to David W. Bates .

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Competing interests.

C.S., K.H., N.R., and C.A.S. declare no competing interests. E.Z. reports personal fees from Arkin Holdings, personal fees from Statista and equity from Valera Health, Profility and Hello Heart. R.S. has been an external reviewer for The John A. Hartford Foundation, and is a co-chair for the Health Evolution Summit Roundtable on Value-Based Care for Specialized Populations. M.M. is an independent director on the boards of Johnson & Johnson, Cigna, Alignment Healthcare, and PrognomIQ; co-chairs the Guiding Committee for the Health Care Payment Learning and Action Network; and reports fees for serving as an adviser for Arsenal Capital Partners, Blackstone Life Sciences, and MITRE. C.K. is a Profility Board member and additionally reports equity from Valera Health and MDClone. D.W.B. reports grants and personal fees from EarlySense, personal fees from CDI Negev, equity from Valera Health, equity from Clew, equity from MDClone, personal fees and equity from AESOP, personal fees and equity from Feelbetter, equity from Guided Clinical Solutions, and grants from IBM Watson Health, outside the submitted work. D.W.B. has a patent pending (PHC-028564 US PCT), on intraoperative clinical decision support.

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Silcox, C., Zimlichmann, E., Huber, K. et al. The potential for artificial intelligence to transform healthcare: perspectives from international health leaders. npj Digit. Med. 7 , 88 (2024). https://doi.org/10.1038/s41746-024-01097-6

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• Published: 27 October 2022

Sanfilippo syndrome: consensus guidelines for clinical care

• Nicole Muschol 1 ,
• Roberto Giugliani 2 ,
• Simon A. Jones 3 ,
• Joseph Muenzer 4 ,
• Nicholas J. C. Smith 5 ,
• Chester B. Whitley 6 ,
• Megan Donnell 7 ,
• Elise Drake 8 ,
• Kristina Elvidge 7 ,
• Lisa Melton 7 ,
• Cara O’Neill   ORCID: orcid.org/0000-0002-9377-259X 8 on behalf of

MPS III Guideline Development Group

Orphanet Journal of Rare Diseases volume  17 , Article number:  391 ( 2022 ) Cite this article

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Sanfilippo syndrome is a group of rare, complex, and progressive neurodegenerative lysosomal storage disorders that is characterized by childhood dementia. The clinical management of patients with progressive neurological decline and multisystem involvement requires a multidisciplinary team with experience in the management of neurodegenerative disorders. Best practice guidelines for the clinical management of patients with these types of rare disorders are critical to ensure prompt diagnosis and initiation of appropriate care. However, there are no published standard global clinical care guidelines for patients with Sanfilippo syndrome. To address this, a literature review was conducted to evaluate the current evidence base and to identify evidence gaps. The findings were reviewed by an international steering committee composed of clinical experts with extensive experience in managing patients with Sanfilippo syndrome. The goal was to create a consensus set of basic clinical guidelines that will be accessible to and informed by clinicians globally, as well as providing a practical resource for families to share with their local care team who may not have experience with this rare disease. This review distills 178 guideline statements into an easily digestible document that provides evidence-based, expert-led recommendations for how to approach common management challenges and appropriate monitoring schedules in the care of patients with Sanfilippo syndrome.

Sanfilippo syndrome (mucopolysaccharidosis type III [MPS III]) is a group of inherited lysosomal storage disorders, manifesting progressive central nervous system (CNS) and systemic disease in childhood, with progressive neurocognitive deterioration and loss of functional abilities, and premature death [ 1 ]. There are four autosomal recessive subtypes (types A, B, C, and D) of Sanfilippo syndrome. Each subtype is caused by a deficiency of a different enzyme that degrades the ubiquitous glycosaminoglycan (GAG) heparan sulfate (Table 1 ), which leads to substrate accumulation and cellular dysfunction [ 2 ].

The combined estimated prevalence of Sanfilippo syndrome (types A, B, C, and D) is between 1:50,000 and 1:250,000 depending on the population studied [ 3 ]. Sanfilippo syndrome type A is the most common subtype globally; however, the prevalence of subtypes can vary depending on region, with Sanfilippo syndrome type A being more prevalent in Northern Europe and Eastern Europe than in Mediterranean countries [ 4 , 5 , 6 ]. In contrast, Sanfilippo syndrome type B is the most prevalent subtype in Southern Europe [ 4 , 7 ]. Sanfilippo syndrome types C and D are much less common overall, with estimated global incidences of 1:1,500,000 and 1:1,000,000, respectively [ 1 ]. However, the total number of patients with Sanfilippo syndrome is most likely underestimated owing to delayed or missed diagnoses, particularly for the most slowly progressing phenotypes.

The age at onset and extent and rate of progression in patients with Sanfilippo syndrome vary greatly between those with different subtypes (ie types A, B, C, and D) and within those with the same subtype (eg type A only). The behavioral, cognitive, and physical findings in patients with Sanfilippo syndrome present as a clinical spectrum from early-onset, rapidly progressive disease with death in late childhood and adolescence, to slower progressing forms that present in later childhood with survival into adulthood. In rare cases, more indolent disease with onset in adulthood is also observed in patients with Sanfilippo syndrome [ 2 ]. The natural history of Sanfilippo syndrome, while traditionally considered across three broad symptomatic phases, remains variable between individuals and is best considered as a phenotypic continuum. Typical disease manifests in patients between 1 and 4 years of age with presentation of mild global developmental or speech delay, usually after a period of normal development with somatic manifestations such as recurrent ear, nose, and throat (ENT) disease and/or bowel disturbance [ 2 ]. Behavioral difficulties include: hyperactivity, (hyper) orality and/or preservative chewing, temper tantrums, lack of fear (for danger), disobedience or unresponsiveness to discipline, and destructive behavior [ 8 , 9 , 10 , 11 ]. Physical manifestations in patients with Sanfilippo syndrome can include musculoskeletal, respiratory, gastrointestinal, cardiovascular complications, vision and hearing loss, and dental issues; these manifestations can further exacerbate the neurocognitive and behavioral challenges in these patients [ 2 , 9 , 12 ]. In the later phase of Sanfilippo syndrome, patients show a decline in engagement with their environment, dementia, and progressive loss of motor function. Patients may develop seizures, dysphagia, and become fully bedridden [ 2 , 13 , 14 , 15 ]. For patients with severe forms of Sanfilippo syndrome, death usually occurs within their second decade of life [ 2 , 16 , 17 , 18 ]. In contrast, patients with attenuated phenotypes of the disorder have a more variable life span, in rare cases surviving into their seventh decade of life [ 14 , 19 ].

Patient care requires a collaborative specialist health and community-based multidisciplinary team with experience in the management of Sanfilippo syndrome. There is currently no disease-modifying therapy available for patients with Sanfilippo syndrome. However, disease-specific therapies for Sanfilippo syndrome are being studied (including forms of enzyme replacement therapy, substrate reduction therapy, hematopoietic stem cell transplantation, and gene therapy), with some reaching the mid-to-late stages of clinical development. In lieu of these emergent therapies, management focuses on supportive interventions to maintain function, optimize ability, and maximize quality of life for patients with Sanfilippo syndrome and their families.

Best practice guidelines for the clinical management of rare diseases are critical to ensure prompt diagnosis and initiation of appropriate care. Such guidelines allow physicians and other healthcare professionals to make recommendations based on the best available evidence, to improve the consistency of diagnosis and clinical management across treatment centers, and to enable affected families to make informed decisions regarding therapy. For patients with Sanfilippo syndrome, there are currently no published, standard global clinical care guidelines.

Here, a collaboration between Cure Sanfilippo Foundation (USA) and Sanfilippo Children’s Foundation (Australia) was initiated in mid-2017 to investigate current best practice in the clinical management of patients with Sanfilippo syndrome. A literature review and gap analysis were conducted to evaluate the current evidence base, and the findings were reviewed by an international steering committee consisting of clinical experts with extensive experience in managing patients with Sanfilippo syndrome. The goal was to create a consensus set of basic clinical guidelines for patients with Sanfilippo syndrome that will be accessible to and informed by clinicians globally, as well as providing a practical resource for families to share with their local care team who may not have experience with this rare disease. Here, 178 guideline statements are distilled into an easily digestible document that provides recommendations based on evidence and consensus clinical expertise for how to approach common management challenges in the care of patients with Sanfilippo syndrome. This review is a first step in establishing basic care guidance and will require updates as Sanfilippo syndrome becomes further characterized and should new therapies become available.

A consultative survey-based technique was used to reach consensus on best practice for the management of patients with Sanfilippo syndrome. An overview of the consensus process is shown in Fig.  1 .

Flow chart for the development of consensus guideline statements. *One statement was subsequently refined by the steering committee during development of the guidelines

A steering committee was formed, consisting of clinical experts from Australia (including members of Sanfilippo Children’s Foundation), Brazil, Germany, the UK, and the USA (including members of Cure Sanfilippo Foundation), each with extensive experience in managing patients with Sanfilippo syndrome. A comprehensive literature review and gap analysis was conducted by members of the steering committee to consolidate the best available published information on the management of patients with Sanfilippo syndrome and to identify evidence gaps. The search terms used are detailed in the supplemental material. Publications reviewed in detail included any published article containing information on patients with Sanfilippo syndrome (types A, B, C, and D), including articles referencing mucopolysaccharidoses in general to delineate information specific to Sanfilippo syndrome.

A network of expert clinicians was invited to join a Guideline Development Group to consider the findings of the literature review and draft initial guideline statements for their area of expertise. In addition to the steering committee members, the Guideline Development Group included 29 clinicians (35 in total) with experience of Sanfilippo syndrome from nine countries (Additional file 1 : Table S1). Collectively, the expert clinicians represented the following focus areas: neurology, metabolic and/or genetic diseases, orthopedics, gastroenterology, ophthalmology, cardiology, dentistry, ENT (including audiology), rehabilitative therapies (speech therapy, occupational therapy, behavioral therapy, and physical therapy), developmental pediatrics, anesthesiology, endocrinology, and integrative medicine (including nutrition and supplements). A total of 185 draft guideline statements were developed by the Guideline Development Group and refined or expanded upon by the steering committee. The draft guideline statements were sent to 166 clinicians from five continents with a survey asking them to rate their level of agreement with each statement on a 5-point Likert scale, as follows: Strongly agree, Agree, Neutral, Disagree, or Strongly disagree. They were also given the option ‘Not my area of expertise’ and asked to provide comments, particularly if they disagreed with a statement.

Consensus was defined as ≥ 75% of responses being ‘Strongly Agree’ or ‘Agree’, excluding responses of ‘Not my area of expertise’. This consensus threshold was determined by a literature review and applied to the rare disease field by the steering committee. The most common definition of consensus for Delphi studies is percent agreement, with ≥ 75% being the median threshold to define consensus [ 20 ]. No participants were compensated for their involvement.

Responses were received from 64 clinicians representing 21 specialty areas. Clinicians were based in 14 countries across five continents, as follows: 29.7% (n = 19) in North America, 26.6% (n = 17) in Europe, 23.4% (n = 15) in Australasia, 12.5% (n = 8) in South America, and 7.8% (n = 5) in Asia. Of the clinicians surveyed, 59% (n = 38) had cared for ≥ 10 patients with Sanfilippo syndrome in their career, and 28% (n = 18) had cared for > 30 patients with Sanfilippo syndrome. Consensus (defined as ≥ 75% responses of ‘Strongly Agree’ or ‘Agree’, excluding ‘Not my area of expertise’) was reached for 173 (94%) of 185 statements. After a steering committee review of the 12 non-consensus items, consensus on four of the statements was not reached and they were omitted. The remaining eight statements were revised based on comments from participants and recommendations from the steering committee. The eight revised were then distributed to the same global clinical email list. Of these eight statements, consensus was reached for five, while three were removed. A full list of all guideline statements and their level of consensus can be found in Additional file 1 : Table S2.

Following the consensus-forming process, the steering committee convened to review the 178 guideline statements and discuss how to distill them into a practical and user-friendly format. As part of this process, consensus recommendations were divided into 156 core statements that tackle the most pressing needs faced by patients with Sanfilippo syndrome, and 22 supplemental statements that address some of the less common aspects of diagnosing and managing the disease, or areas that require further evidence. Additional refinement of the resulting guidance by the steering committee’s clinical experts was made in select areas, based on their collective clinical experience and consideration of any risks associated with recommended procedures. These few instances are noted where they occur.

Optimal management relies on early diagnosis

Early diagnosis of Sanfilippo syndrome is critical to ensure the optimal care for patients and their families by enabling access to specific supportive interventions to maximize peak abilities, slow rate of decline, and improve quality of life. In addition to accessing appropriate education and developmental therapies, early diagnosis enables patients to participate in clinical trials and/or receive treatments as they emerge, and affords timely genetic counseling of affected families. However, diagnoses delayed by > 2 years are not uncommon in patients with Sanfilippo syndrome [ 21 , 22 , 23 , 24 ]. Potential reasons for delays include a lack of disease awareness, the absence or subtle presentation of somatic symptoms, and neurological symptoms that can be mistakenly considered as idiopathic developmental delays and behavioral challenges [ 23 ]. Furthermore, Sanfilippo syndrome is not included in newborn screening programs and patients often receive diagnoses such as idiopathic developmental delay, attention deficit hyperactivity disorder (ADHD), and/or autism without sufficient medical workup to identify Sanfilippo syndrome as the underlying genetic disorder [ 18 , 25 , 26 ].

A recent consensus-forming process identified eight signs and symptoms that presented early in neonates and infants that may, alone or in combination, raise suspicion of Sanfilippo syndrome [ 27 ]. Such signs and symptoms included coarse facial features, persistent hirsutism and/or prominent eyebrows, which have been reported as signs that are suggestive of Sanfilippo syndrome and should prompt referral to a metabolic physician and/or developmental specialist [ 27 ]. Somatic signs should also be viewed in the context of neurocognitive features. For example, early somatic signs that are not specific to Sanfilippo syndrome (eg frontal bossing and macrocephaly) become noteworthy when present alongside neurocognitive features (eg speech delay). Similarly, while episodic irritability and gastrointestinal discomfort, umbilical or inguinal hernia, and upper respiratory congestion are considered prevalent among neonates and infants [ 28 ], any of these conditions, including those listed previously, should raise suspicion of MPS diseases but particularly for Sanfilippo syndrome when present alongside the characteristic neurobehavioral features. Table 2 shows a list of neurological and somatic features that (alone or in combination) should raise suspicion of Sanfilippo syndrome. Sanfilippo syndrome should be considered in patients of all ages, not only young children, since slower progressing forms of the disorder are noted. For example, investigation for Sanfilippo syndrome is warranted in adults who show signs of early-onset dementia, vision loss with retinitis pigmentosa, and/or adult-onset cardiomyopathy [ 29 ]. Where such suspicion exists, screening and/or diagnostic tests should be initiated by the primary care provider to avoid delay of diagnosis, in conjunction with referral to an appropriate specialist.

Confirming a diagnosis of Sanfilippo syndrome

In individuals with clinical features suggestive of Sanfilippo syndrome, confirmation of a diagnosis requires at least two biochemical or genetic markers of the disorder to be present: evidence of GAG accumulation (eg increased total GAGs or the more specific component substrate, heparan sulfate, in the urine or blood), decreased lysosomal enzyme activity, and/or evidence of pathogenic or likely pathogenic variants via molecular testing [ 30 , 31 ].

GAG analysis

Analysis of urine GAGs using quantitative and qualitative approaches in a first morning void sample are accepted biochemical diagnostic tests, with a sample from a random time also being acceptable. A sterile sample is not required. Quantitative analysis of urine for the presence of GAG biomarkers using the spectrophotometric compound dimethylmethylene blue is often used as a first-line screen for MPS disorders [ 32 , 33 , 34 , 35 ]. The use of age-related reference ranges is strongly recommended owing to the natural decrease in GAG levels with age, both in affected patients and healthy individuals. The recommended qualitative GAG assay is GAG electrophoresis [ 31 , 36 , 37 ]. Notably, however, both quantitative and qualitative urine GAG tests can be insensitive, particularly if the urine is dilute, and cannot rule out Sanfilippo syndrome owing to the significant rate of false-negatives [ 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. Therefore, in cases of increased clinical suspicion with a negative urine GAG screen, follow-up with enzyme analysis or genetic testing is recommended. Semi-quantitative urine screening assays using cationic dyes on filter paper (eg the Berry spot test) have relatively high rates of false-positives and false-negatives and should no longer be used [ 30 ].

The analysis of GAGs is being replaced by the analysis of specific GAG species (eg heparan sulfate) using tandem mass spectrometry because of increased sensitivity and specificity to these species [ 38 ]. Tandem mass spectrometry is now routinely used in some laboratories and should become the predominant strategy for GAG analysis in the future.

Enzyme analysis

As above, Sanfilippo syndrome is caused by deficiencies in one of four enzymes that are associated with a defect in heparan sulfate metabolism [ 39 , 40 , 41 , 42 ]. Enzymatic analysis using blood leukocytes or cultured fibroblasts is the recommended gold standard for confirmation of diagnosis of Sanfilippo syndrome and can be considered as a first-line test, particularly when there are difficulties obtaining a suitable urine sample and/or shipping in adequate conditions (ie < 4 °C, delivered within 24 h) [ 43 ]. At the very least, enzyme analysis should be performed in patients with increased GAGs (heparan sulfate) or if clinical suspicion is increased [ 43 ]. Enzyme activity and the presence of heparan sulfate fragments can also be measured by mass spectroscopy in dried blood spots (DBS), which offers considerable practical advantages (eg sample collection, storage, and transport), and multiple enzyme activity tests can be performed on a single sample [ 44 , 45 ]. In addition, parameters such as sample viscosity, hematocrit level, and contamination during the drying process can affect the sensitivity, reproducibility, and overall accuracy of DBS measurement [ 46 ]. Therefore, a deficient enzyme result in DBS samples should be confirmed by an enzyme assay in leukocytes or fibroblasts, and/or by molecular genetic analyses [ 31 ]. False-negatives have not been reported in newborn screening pilot studies with this methodology, but clinical suspicion beyond the newborn period should always trigger laboratory testing.

Multiplex tandem mass spectrometry provides the potential to assay all enzymes simultaneously via high-throughput screening [ 47 ]. Alternatively, each enzyme can be assessed individually and ordered in a sequence according to the relative frequency of disease subtypes in the region; however, this assay is labor intensive and good quality control is essential [ 43 ]. The clinical features of Sanfilippo syndrome are similar to other conditions, such as multiple sulfatase deficiency and mucolipidosis. Therefore, if the sulfatase enzymes for Sanfilippo syndrome type A (heparan- N -sulfatase) or type D (N-acetylglucosamine 6-sulfatase) are deficient, then at least one other sulfatase should be assayed to rule out multiple sulfatase deficiency [ 31 ]. Conversely, if multiple lysosomal enzymes are elevated, the diagnosis of mucolipidosis should be suspected and confirmed by DNA testing.

Molecular genetic testing

A suspected diagnosis of Sanfilippo syndrome can be confirmed by molecular genetic testing or mutation analysis [ 31 ]. Molecular genetic testing should be offered to all patients as it enables cascade molecular screening of undiagnosed siblings or extended family members and family members who are carriers [ 31 ], thereby enabling appropriate genetic counseling and informed family planning [ 30 ]. In addition, the findings of molecular testing may inform clinical expectations of disease progression according to the pathogenicity of the mutation and knowledge regarding the correlation of genotype with phenotype [ 30 ]. Molecular testing results may also impact the patient’s eligibility for clinical trials and future therapies.

In instances where a patient’s primary diagnosis is made based on a molecular genetic diagnosis, a confirmatory biochemical assay should be conducted to confirm the pathogenicity of the mutations [ 48 , 49 ]. When a patient is identified as homozygous for a mutation that is pathogenic for Sanfilippo syndrome or heterozygous for two known pathogenic mutations, a diagnosis can be made with reasonable confidence if the patient has a clinical phenotype consistent with Sanfilippo syndrome.

Prenatal diagnosis

Prenatal diagnosis is feasible for Sanfilippo syndrome in the context of a known familial diagnosis. The main methods used to collect material for prenatal testing are amniocentesis and chorionic villus sampling, which enable biochemical and molecular testing of fetal-derived tissues. If there is an older sibling with a confirmed diagnosis of Sanfilippo syndrome who has two known mutations, prenatal diagnosis may be made with molecular testing alone [ 1 , 27 , 44 ].

Newborn screening

Newborn screening provides the opportunity to diagnose patients as early as possible and enable prompt intervention with optimal outcomes when disease-specific therapies are approved [ 31 ]. Given the progressive and seemingly irreversible nature of the neurological manifestations of Sanfilippo syndrome, the adoption of all available measures to detect patients as early as possible should become standard practice. Most newborns with Sanfilippo syndrome are asymptomatic at birth; therefore, the identification of biochemical or genetic markers of Sanfilippo syndrome in newborns is crucial [ 50 ].

A suitable method for the screening of newborns is one that is rapid, cost-effective, sensitive, and widely available [ 50 ]. Newborn screening for MPS disorders has been studied with several methods, including GAG assay in urine, GAG assay in DBS with ultra-performance liquid chromatography combined with tandem mass spectrometry, fluorometric enzyme assay, digital microfluidics enzyme assay, and enzyme and/or substrate assay with tandem mass spectrometry (MS/MS) [ 50 ]. Overall, the recommended approach for the screening of MPS disorders is the analysis of enzyme activity in DBS with MS/MS or fluorometry to identify MPS subtypes, which is not possible with GAG assays. Newborn screening with molecular genetics tools is being considered; however, these tools are less readily available compared with biochemical testing [ 50 ].

In countries with newborn screening facilities, Sanfilippo syndrome is generally not included in routine screening programs; however, pilot studies for Sanfilippo syndrome types A and B are in progress. As disease-specific therapies become available and improve the lives of patients with Sanfilippo syndrome, the ethical and clinical imperative for early (pre-symptomatic) diagnosis will strengthen. Moreover, although newborn screening cannot determine disease severity, such programs provide timely information that may inform planning for families, even prior to the availability of commercially approved treatments.

General principles and goals of management

In the absence of a disease-modifying treatment for Sanfilippo syndrome, the primary goal of management should be to optimize the quality of life for patients and their families. This requires a holistic approach that considers the wide-ranging and complex medical needs of patients with this condition. A key step in this process is the establishment of a multidisciplinary team of healthcare professionals to work collaboratively and in partnership with patients with Sanfilippo syndrome and their families. This multidisciplinary team would include (but is not limited) to physicians, nurses, therapists (eg physical, occupational, and speech), dieticians, psychologists, social workers, special educators, and counselors. A supervising clinician should oversee the coordination of care. Comprehensive care should be initiated as early as possible, ideally immediately after diagnosis, and the frequency of clinic visits and assessments should be tailored to meet the individual needs of each patient with Sanfilippo syndrome and their family. Frequent communication with families is important to align on care goals and plans, and to ensure that the best interests and values of patients and their families remain at the heart of the decision-making process.

Different assessments and interventions are required for patients with Sanfilippo syndrome depending on their level of disease progression (Table 3 ), and treatment plans should be modified according to each patient’s needs. For example, during the pre- and early symptomatic time frames, it is important to establish a multidisciplinary care team, initiate supportive care measures, conduct forward planning with families around future care needs, and provide genetic counseling as a part of family planning. As a patient’s disease progresses, supportive care measures need to be increased to alleviate the burden of symptoms and to support engagement in everyday activities as much as possible. For patients showing signs of pain, distress or behavioral changes of undetermined etiology, systemic assessments of likely causes of pain are recommended (Table 4 ). In the later stages of the disease, the maintenance of quality of life and prevention of complications become the priorities of care.

In addition to their impact on the patient, neurodegenerative conditions such as Sanfilippo syndrome can have a strong negative impact on the psychosocial functioning and quality of life of family members [ 51 , 52 , 53 , 54 , 55 ]. Parents and caregivers face potentially traumatic medical events followed by short- and long-term stress [ 56 ], putting them at risk of developing parental post-traumatic stress disorder (PTSD) [ 56 , 57 , 58 ]. For example, 22% of parents of children with Sanfilippo syndrome in the Netherlands were found to be suffering from PTSD, compared with 3.8% of parents in the general population of the same country [ 59 ]. The presence of parental PTSD can, in turn, have a significant influence on the psychological wellbeing of the affected child [ 60 ]. Thus, the adoption of a trauma-informed approach to caring and supporting families affected by Sanfilippo syndrome is imperative [ 61 ].

Managing the neurological challenges of Sanfilippo syndrome

Monitoring of neurodevelopment.

Progressive CNS degeneration is a characteristic feature in patients with Sanfilippo syndrome, with neurological plateau and eventual regression following initial normative gains in neurodevelopment [ 1 , 62 ]. Clinical heterogeneity exists between and within the four disease subtypes and the rate of neurocognitive decline varies. While broad genotype–phenotype correlations have been recognized in some cases [ 15 ], these are not universal [ 1 , 62 ]. Patients should therefore undergo detailed neurological evaluation at diagnosis and regular monitoring (eg every 6–12 months) thereafter to detect changes in cognition, motor function, and behavior.

The most well-characterized neurocognitive phenotypes are Sanfilippo subtypes A and B. In these forms of the disease, patients generally continue to acquire cognitive skills until the age of 2.5–4 years depending on the subtype and severity phenotype [ 62 ]. Data for Sanfilippo syndrome types C and D are limited [ 63 ]. However, depending on phenotype, the timing of developmental plateau and pace of decline can vary. Speech and language delay are the most frequent initial symptoms, and language delay may be apparent by the age of 2 years, before cognitive decline starts [ 21 , 64 ]. Conductive hearing loss secondary to middle ear disease is commonly comorbid, along with the development of high frequency sensorineural hearing loss [ 21 ], and further impacts the acquisition of critical early language skills. Indeed, in this context, the effective management of middle ear disease and sensorineural hearing loss typically results in significant improvements. Monitoring of neurocognitive function is recommended on an ongoing basis (or at a frequency appropriate to each individual’s needs) to help families identify areas of strength and interval loss of skills. In addition, this monitoring will help to support discussions focused on helping families adjust to progression of the disorder, educational needs, and supportive interventions in the later phases of the disease. There are many psychometric measures that can be used to evaluate cognitive function in patients with Sanfilippo syndrome [ 65 ]. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) is one of the most frequently used in clinical studies [ 62 ]. However, use of a specific instrument for clinical care purposes did not reach consensus in our survey. Clinicians may use an available tool that is best suited for monitoring their individual patient over time; recognizing that use of measures that align with published studies may allow for a more informed comparison of the patient’s results with existing disease natural history data.

In addition to assessing neurocognitive function, magnetic resonance imaging (MRI) of the brain should be conducted at baseline and as clinically indicated. Neurodegeneration in patients with Sanfilippo syndrome can be represented by decreases in the volume of cortical and subcortical parenchyma, with secondary increases in ventricular volume on MRI over time [ 63 ]. These changes occur in parallel with cognitive decline and are much more severe in patients with rapidly progressing phenotypes than in those with slowly progressing phenotypes [ 64 ]. Triggers for ordering an MRI of the brain, beyond the baseline assessment, may include extreme behavioral changes, unexplained pain or distress, suspicion of headaches, suspicion of elevated intracranial pressure, and sudden neurological or functional declines. Opportunistic neuroimaging may also be considered during anesthesia for another reason, provided that the risks and benefits are weighed and discussed with the family.

Motor function

Assessment of gross motor and fine motor function is recommended at diagnosis of Sanfilippo syndrome and then every 6–12 months, or more frequently if clinically indicated. Fine motor skills reach a plateau at approximately 2–3 years of age in patients with Sanfilippo syndrome types A and B with typical progression of the disorder (mirroring cognitive decline), whereas development of gross motor skills tends to be preserved until later. In this regard, one study of patients with Sanfilippo syndrome types A, B, and C reported the onset of clumsiness in walking at a median age of 7 years, 7.5 years, and 9 years, respectively, and loss of unassisted sitting at 10.5 years, 14 years, and 13.5 years, respectively [ 22 ]. Given cognitive impairment and hearing loss, difficulties in following instructions together with poor imitative skills may impair the ability of patients with Sanfilippo syndrome to perform motor tasks after this age.

Walking and gait should be assessed at baseline then every 6–12 months, or as needed. Clinicians should be particularly mindful of functional impairments and the development of movement disorders such as dystonia, ataxia, and dyskinesias (including tics, myoclonus, and choreoathetosis). As the disease progresses, patients may require more time to initiate or complete a task owing to the development of motor apraxia and challenges with motor planning. This additional time should be accommodated in clinical exams, formal testing, and during educational and therapeutic activities. Consideration should be given to the needs for medical equipment such as orthotics and bracing, and when to refer to orthopedics, physiotherapy, or other supportive care functions.

Considerations for neurobehavioral, psychological, and psychiatric care

Changes in neurocognition at 2–4 years of age typically coincide with the appearance of behavioral difficulties, including hyperactivity, hyperorality and/or preservative chewing, temper tantrums, disobedience or unresponsiveness to discipline, decreased attention, and severe sleep disturbance [ 4 , 8 , 10 , 19 , 66 , 67 , 68 ]. Most patients with Sanfilippo syndrome develop autistic-like behaviors (primarily social and emotional abnormalities from approximately 4 years of age [ 25 , 69 ]), and as cognitive function declines, many patients display disinhibited behaviors [ 70 ]. For patients with slowly progressing disease who survive into adulthood, reported behavioral problems include motor restlessness, screaming, sensitivity to touch or temperature changes, anxiety, crying fits, aggressive behavior, stereotypic speech, and irritability [ 19 ]. Another report found that adults with Sanfilippo syndrome tend to engage less in interactions and become withdrawn [ 9 ].

The management of behavioral symptoms requires a holistic approach of understanding the behavior in the context of the cognitive skill level, creating a safe environment at home and school for the patient, and providing a routine and structure in addition to any pharmacologic approaches [ 9 , 71 ]. Developmental testing should be conducted in an environment familiar to the patient by a tester who has an established rapport with the patient and has familiarized themselves with the behavioral characteristics of Sanfilippo syndrome prior to testing. When evaluating and monitoring adaptive behavior skills, the Vineland Adaptive Behavior Scale should be used as at least one of the measures [ 72 , 73 , 74 ]. When considering behavior-modifying medications, careful consideration of the following is needed to formulate a proper treatment strategy: any physical problem (eg pain), musculoskeletal problems, gastrointestinal disturbances, seizures, dental problems, and communication challenges.

The identification of negative stimuli (eg pain, an unfamiliar situation or environment, or the association of an unpleasant feeling with a specific location) is needed to prevent or mitigate abnormal behavior [ 9 , 71 ]. The input of parents and caregivers should be encouraged to help calm and comfort the patient when completing necessary medical tests and exams. If necessary, tests may be conducted under anesthesia when coordinated with other procedures.

Early identification of behavioral changes and sleep problems will help to enable effective management and referral to appropriate specialized services [ 4 , 15 ]. Regular neurologic assessments are recommended at baseline and then every 6–12 months, and more frequently if clinically indicated [ 18 ]. Evaluations should monitor the appearance or changes in sleep disturbances, seizure activity, neuromuscular tone, movement disorders, and behavior.

The identification of psychiatric symptom clusters in the context of the developmental age-equivalent profile of each patient is helpful when considering interventions to manage the neurobehavioral aspects of Sanfilippo syndrome. These clusters include sleep, ADHD and autistic behaviors, social communication difficulties, speech and language difficulties, sensory difficulties, and anxiety. Applied behavioral analysis therapy, where available and tailored to the individual patient, should be supported to enhance communication skills, maintain motor abilities, reduce unsafe behaviors, and reduce behaviors that interfere with learning and engagement as it has been found to be beneficial for some patients with Sanfilippo syndrome [ 75 ].

Several groups of behavior-modifying medications have been administered to patients with MPS disorders; however, published evidence for the use and long-term effectiveness of these agents in patients with Sanfilippo syndrome is limited [ 9 ]. Therefore, the prescription of psychiatric medication targeted to mitigate behavioral symptoms should be accompanied by an evaluation of contraindicated risks. Such evaluation is particularly important given that Sanfilippo syndrome is a multisystem disease and the impact of psychotropic medication on cardiac, hepatic, and renal systems needs to be taken into account. Use of stimulant medications, mood stabilizers, antipsychotics, and antianxiety drugs may be considered on a case-by-case basis and with short-term trial periods following a review of the potential risks and benefits with the patient’s family.

Seizure management

Seizures have been reported in patients with MPS disorders in which GAG accumulation in the brain is speculated to trigger alterations in neuronal connectivity and signaling, and release of inflammatory mediators [ 4 , 76 ]. Approximately 26–52% of patients with Sanfilippo syndrome will develop seizures and epilepsy in the later stages of the disease [ 4 , 14 , 15 , 68 , 76 ]. While the prevalence of seizures does not differ greatly between patients with the four subtypes of Sanfilippo syndrome, the age of onset of seizures appears to be somewhat earlier in patients with type A than in those with other subtypes [ 4 , 14 , 15 , 17 , 19 , 22 , 77 ], and the incidence of seizures has been found to increase with advancing neurocognitive deterioration [ 4 ].

Patients with Sanfilippo syndrome typically present with generalized tonic–clonic seizures [ 19 , 22 , 78 , 79 ]. A study of electroencephalography (EEG) records of patients at different stages of Sanfilippo syndrome found that progressive EEG changes correlated with age and disease progression [ 80 ]. While patients younger than 3 years had normal background activity while awake, slowing of occipital-dominant rhythm and background activity at wakefulness could be observed after 6 years of age and became more severe after 11 years of age. Non-convulsive status also was noted in a couple of patients [ 80 ]. EEG abnormalities during sleep have also been reported [ 79 ]. Nocturnal seizures can disrupt sleep hygiene, which in turn can exacerbate and contribute to diurnal somnolence, disturbed concentration, and neurobehavioral lability [ 76 ].

Optimal management of patients with epileptic seizures requires a correct diagnosis. Clinicians should have a high index of suspicion in monitoring for epileptic activity (convulsive and non-convulsive) in patients with Sanfilippo syndrome. However, seizures can be difficult to detect in patients with Sanfilippo syndrome as they often become evident by alterations and/or abnormalities in mental status, behavior, and/or cognition, which are inherent features of the disease [ 81 , 82 ]. The occurrence of absence seizures and non-convulsive status epilepticus can be subtle and difficult to monitor. A diagnostic workup for seizures in patients with Sanfilippo syndrome should include electrophysiological examination by EEG, and prolonged video EEG or in-home mobile EEG may be warranted to detect more subtle seizure activity and nocturnal seizures.

Both convulsive and non-convulsive epilepsy should be adequately treated according to the patient's individual needs and medication history. Literature discussing the treatment of epileptic seizures in patients with Sanfilippo syndrome is limited. Anecdotal evidence based on the experience of experts in the treatment of epilepsy in patients with MPS disorders indicates there are not clinically significant differences in seizure control and management between patients with Sanfilippo syndrome and other patients with epilepsy [ 76 ]. Therefore, standard protocols for the treatment of seizures should be followed [ 53 ]. Preference should be given to anti-epileptic drugs with fewer drug–drug interactions that do not require the monitoring of therapeutic drug levels.

Sleep alterations are an almost constant feature of Sanfilippo syndrome, affecting 87–92% of patients [ 67 , 83 ]. Features include difficulties with settling, frequent nocturnal waking and wandering, and greater daytime sleep compared with healthy individuals [ 2 , 10 , 84 ]. The unrelenting nature of sleep disturbances places a heavy burden on both the patient and their family, and can cause great distress [ 10 , 84 ].

In patients with sleep disturbance, medical workup should include consideration of the presence of disordered movement or seizure activity [ 85 ], iron deficiency in the setting of restless legs, pain or intercurrent illness, esophageal reflux, dental disease, and disordered breathing or sleep apnea during sleep. Sleep disturbance should be addressed with a multimodal approach that includes sleep hygiene counseling, implementing behavioral strategies, addressing the safety of the environment (eg securing the door to prevent harm from wandering, removing items that may cause choking, removing or covering hard surfaces, enclosed specialty beds, and avoiding furniture that could be toppled over), treating circadian rhythm disturbance, and other comorbid medical factors. The use of sleep diaries is encouraged for monitoring changes, evolution of sleep disturbance, and response to interventions.

Sleep apnea is well described as a cause of sleep disturbance in patients with MPS disorders [ 86 , 87 ]. A history of sleep apnea and snoring should be sought in all patients with Sanfilippo syndrome who also have sleep disturbance [ 87 ], and diagnosis and management of sleep apnea should be made under the guidance of a pulmonologist and/or otolaryngologist depending on etiology. If the patient has signs and symptoms of obstructive sleep apnea along with adenoid and/or tonsillar hypertrophy, removal of adenoids and/or tonsils should be performed without delay. This may need to be repeated if tissue regrowth and obstructive sleep apnea recurs later. Continuous positive airway pressure (CPAP) therapy should be considered for patients who display the presence of obstructive sleep apnea that persists after adenoidectomy and/or tonsillectomy. The implementation of CPAP will likely require additional longer-term behavioral or other supports to help increase the patient’s acceptance of the device. The ongoing follow-up of patients who are receiving medication for respiratory and sleep disorders is recommended, the frequency of which will depend on the severity of the respiratory disease and sleep-disordered breathing.

Patients with Sanfilippo syndrome may experience disruption of their circadian rhythm [ 86 , 88 ], which may be partly addressed by melatonin supplementation [ 9 , 10 , 71 ]. If melatonin is started, it is recommended to begin at a low dose (0.5–2 mg) and then be titrated up to higher doses per the patient’s response [ 10 , 89 ]. The typically recommended dose is 2–10 mg at bedtime, but a higher dose is occasionally needed.

Managing the airway

Respiratory management.

Respiratory tract and sinopulmonary infections are common in patients with Sanfilippo syndrome [ 12 ], and respiratory complications such as pneumonia have been reported as the primary cause of death in these patients [ 90 ]. However, behavioral disturbances in patients with Sanfilippo syndrome may mask the typical signs of respiratory infection, leading to diagnosis after the respiratory infection has advanced. Therefore, clinicians should consider a diagnosis of pneumonia in patients with Sanfilippo syndrome and should order early diagnostic radiology when a respiratory infection is suspected, with prompt treatment with antibiotics when pneumonia is confirmed.

As part of routine clinical care, patients with Sanfilippo syndrome should undergo regular clinical assessments and physical examination to facilitate the early detection of respiratory or other complications. These steps should include assessment of vital signs (eg respiratory rate, heart rate, height, and weight) and routine respiratory examination (including the nose and oropharynx). Investigation of clinical history should include sleep hygiene, quality and duration, symptoms of sleep-disordered breathing, history of respiratory symptoms (eg chronic cough), history of pneumonia, history of oral secretions, history of difficulty feeding, history of gastroesophageal disease, and history of nasal secretions and/or nasal congestion. Abnormal findings may prompt measurement of oxygen saturation and non-invasive monitoring of carbon dioxide, if available. Excessive oral secretions may be managed by manual suction and/or medications such as atropine or glycopyrrolate [ 84 , 91 , 92 ].

Routine childhood vaccinations should be given per the standard of care schedule, including annual influenza vaccines. Pneumovax 23 is recommended for patients with Sanfilippo syndrome, in accordance with the guidelines for those who are at increased risk of pneumococcal disease [ 12 ]. While the potential increased risk of serious illness owing to COVID-19 infection in patients with Sanfilippo syndrome is considered likely, there is limited experience in these patients and vaccination is recommended in line with accepted global protocols.

Anesthesia and peri-operative care

Patients with Sanfilippo syndrome may require anesthesia for surgical interventions (eg dental extractions and tonsillectomy) to help manage their disease or to carry out evaluations such as MRI, lumbar puncture, or echocardiography [ 93 , 94 ]. Complications during anesthesia and surgery can occur in patients with Sanfilippo syndrome [ 94 , 95 ], albeit typically at a lower rate than in patients with other MPS disorders [ 96 ]. A retrospective analysis of 126 cases of anesthesia in 37 patients with Sanfilippo syndrome found that the most common anesthesia-related complications were bradycardia or tachycardia (2.4% of anesthesia events), respiratory insufficiency (1.6%), hypoxemia (1.6%), and atelectasis (1.6%) [ 96 ].

To mitigate the respiratory risks in patients with Sanfilippo syndrome, sedation and anesthesia events should always be conducted in the hospital setting with experienced anesthesia personnel available and ready to manage complex airway emergencies. In situations where a procedure or evaluation would be most efficiently and humanely conducted under anesthesia, the number of such anesthesia events should be minimized within reason by combining procedures and coordinating efforts with the multidisciplinary team, as much as possible.

For patients with behavioral and cognitive challenges, patient-centered accommodations should be considered to ensure their safety and wellbeing before and after anesthesia [ 93 , 94 , 95 , 97 ]. Such accommodations may include: allowing parent/caregiver access to the patient during the induction of anesthesia and upon emergence/recovery; providing a low-stimulus environment with the ability to secure/close doors to reduce the risk of the patient escaping; the use of distraction techniques and items; consideration of safety concerns with regards to impulsivity, hyperactivity, and flight risk; and provision for additional staff to supervise as appropriate to meet the needs of each patient.

Prior to anesthesia, nursing and medical providers should review advanced directives, baseline pain, and comfort care needs with the patient and their family. Pre-operative anesthetic review and airway assessment should be conducted prior to the day of the scheduled procedure to allow time to have any necessary equipment and staff available for the sedation event. Unless contraindicated, chronic medications should be given on the day of anesthesia within the confines of fasting guidelines, particularly anticonvulsants and neurobehavioral medications.

While anesthesia-related airway issues are less common in Sanfilippo syndrome than in other mucopolysaccharidoses, when they do occur, they can be serious.

When preparing for anesthesia in a patient with Sanfilippo syndrome, providers should be prepared for a potentially difficult laryngoscopy and intubation [ 93 , 94 , 95 , 97 ]. If an upper airway obstruction which may complicate intubation is suspected, a pre-operative flexible endoscopy (nasopharyngolaryngoscopy) is recommended in order to inspect the upper airway. Laryngeal mask airway is a good alternative to tracheal intubation for many patients in whom a native airway is not feasible or if the procedure is short and non-invasive (eg MRI scan). General anesthesia with a native airway (without pharyngeal or laryngeal intubation) may be considered for patients with Sanfilippo syndrome; however, the use of standard airway maneuvers (eg chin lift, shoulder roll, CPAP, and oral or nasal airways) and adjuncts (eg CPAP) may be needed [ 93 , 94 , 95 , 97 ].

Somatic manifestations of MPS III

Ent and audiology considerations.

Hearing loss is common in patients with Sanfilippo syndrome and can contribute to speech delay and behavioral and learning problems [ 9 ]. Hearing loss can be conductive, sensorineural, or mixed due to a combination of dysostosis of the ossicles of the middle ear, inner ear abnormalities, and frequent otitis media and impaired neurological function [ 12 ]. To ensure early detection, ENT examination and audiologic testing should be conducted immediately after diagnosis, with a follow-up at least every 12 months and more frequently if there are recurrent episodes of otitis or suspected changes in hearing. When there is identified hearing loss or otitis media with effusion, follow-up may need to be more frequent based on the individual patient.

When detected, the early and aggressive management of hearing impairment and ear effusion should be performed to optimize language development during critical developmental windows. ENT surgery remains a fundamental therapeutic procedure for reducing the frequency and severity of ear infections, even if the interventions are not curative [ 86 , 98 ]. If a conductive type of hearing loss is detected owing to effusion in the ear (lasting more than 2 months bilaterally or 4 months unilaterally), grommets (ventilation tubes) should be inserted without delay to maximize hearing and reduce symptoms.

Audiology evaluation should include assessments of both air and bone conduction. Where hearing assessment is needed, and behavioral testing is not possible, auditory brainstem response testing under sedation or general anesthesia should be considered. Decisions on the use of hearing devices should be made in close collaboration with the family, and the hearing needs of the patient should always be clearly documented in their records and care plans with accompanying advice on communication and hearing supports, particularly in the educational setting. Standard ‘behind the ear’ hearing aids should be considered for patients with hearing loss. Challenging behavior should not be used as an excuse to dismiss a trial of hearing aids, particularly in the educational setting.

Ear disease may also present with an impairment in balance. Balance problems can significantly impact quality of life, particularly mobility, and may be overlooked in patients who are unable to communicate their symptoms effectively. Considering ear disease as a factor in emerging or worsening balance problems may uncover a potentially treatable etiology. ENT physicians can aid in specialized evaluation of these concerns.

Ophthalmologic considerations

A proportion of patients with Sanfilippo syndrome have affected eyesight, though the timing and progression of visual impairment has not been well studied to date. Pigmentary retinopathy is considered a prominent ocular manifestation in patients with Sanfilippo syndrome [ 29 ], with severity ranging from subclinical electroretinography features to moderate-to-severe clinical disease that leads to problems such as nyctalopia (night blindness) and overall decreased vision [ 99 , 100 , 101 , 102 ]. The corneas of patients with Sanfilippo syndrome type A and type B appear clear but have increased mean fibril diameter and fibril spacing [ 101 , 103 ]. Optic atrophy and disk swelling have also been reported [ 104 ].

Routine ophthalmologic examination is recommended every 12 months and more frequently if clinically indicated. Ophthalmologic assessment should include assessment of vision in both eyes, orthoptic assessment, refraction, examination of anterior and posterior segment of the eye (including examination of the cornea, retina, and optic nerve), and measurement of intraocular pressure. Patients with behavioral challenges may require examination under anesthesia, in which case the risks and benefits must be weighed.

Given that clinical signs of vision loss may be difficult to detect or absent in patients with impaired communication, input from caregivers is essential. An electroretinogram can confirm the diagnosis when retinopathy is suspected owing to symptoms of night blindness or impaired vision in low light, visual field loss or reduction in vision, or signs of pigmentary retinal change, but the benefits of knowing versus the risk of anesthesia must be weighed.

Patients with Sanfilippo syndrome and visual impairment should be provided with access to low-vision supports and services in the home, community, and educational settings. Support for vision impairment should be included in educational settings as part of their individualized educational plan.

Dental care

The dental features of patients with Sanfilippo syndrome are not well described compared with those of other MPS disorders [ 105 ], with disease-specific observations limited to generalized obliteration of pulp chambers and root canals [ 106 , 107 ]. However, patients with MPS disorders are typically considered at high risk of dental disease [ 105 ]. Therefore, basic good oral hygiene is recommended with twice-daily brushing and avoidance of drinking sugary beverages on a regular basis.

Regular dental visits, preventive fluoride applications, and dental treatment must be included in the multidisciplinary team approach. Oral health problems should be ruled out in the setting of behavioral changes, agitation, distress, changes in sleep patterns, changes in eating habits, or a change in oral sensory behaviors.

In patients who have challenges clearing food from the oral cavity or who take daily sweetened liquid medications, water should be offered or teeth wiped after meals and snacks. As brushing the teeth can be challenging in patients who have a sensory aversion to or do not understand this task, supports such as three-sided toothbrushes, bite blocks, and distraction techniques may be helpful. Dental sealants are recommended to prevent and/or arrest dental caries in primary and/or permanent molars, and they should be monitored for integrity at each dental visit and restored as indicated. If sedation is required for dental procedures, dental care should take place in a tertiary care facility with experienced anesthesia staff.

Nutritional and gastrointestinal management

Gastrointestinal disturbances are common in patients with Sanfilippo syndrome and typically include chronic or recurrent non-infectious loose stools and/or constipation [ 12 ]. Stooling issues can be a source of discomfort and distress for patients, which may manifest through an increase in behavioral disturbances, heightened sleep disturbance, or other alternative expressions of pain. To mitigate discomfort and distress, therapeutic maintenance regimens should aim for consistent and adequate stool elimination to maintain the comfort and health of the patient.

Diarrhea is typically episodic for patients with Sanfilippo syndrome but can be persistent in some individuals and can be exacerbated by frequent antibiotic treatment or recurrent infections. The management of diarrhea includes medications when needed (eg synthetic opioids to reduce gut motility). The care plan should note, particularly for all care providers in the educational and therapeutic settings, that non-infectious Sanfilippo syndrome-related diarrhea should not be a cause for exclusion from educational and therapeutic activities.

No specific dietary plan has been studied in Sanfilippo syndrome to guide dietary recommendations, outside of general advice for a healthy diet. Monitoring and restoration of micronutrient deficiencies is recommended to support metabolic functions. Patients should also be monitored for gastroesophageal reflux, which may contribute to increased behavioral distress or increased sleep disturbance. Where present, a trial of anti-reflux medication, diet modification, or a combination thereof should be considered.

Assessment of eating, drinking, and swallowing abilities should be performed by a speech–language–feeding therapist at diagnosis and then monitored at least yearly if clinically indicated. Steering committee clinicians further recommend that primary care providers elicit history regarding any safety concerns with eating, drinking, and swallowing routinely at scheduled visits, prompting further referral as needed. Clinical assessments provide the best information when conducted at mealtimes and in a variety of settings (eg home and school) to observe any accompanying behavioral and cognitive challenges around mealtimes.

Referral to a dietician is recommended for patients with Sanfilippo syndrome who have a substantially self-limited diet, experience weight loss or poor growth, have sensory needs limiting proper nutrition, or experience a decline of oromotor skills that impairs normal caloric intake within a reasonable time frame. Such referral should be made in conjunction with referral to or consultation with a speech–language–feeding specialist. Diet and fluid modifications should be made using the International Dysphagia Diet Standardization Initiative framework ( https://iddsi.org/framework/ ) in consultation with a trained speech–language–feeding therapist. In instances of inadequate nutrition via oral feeding or presence of significant risk of aspiration or history of aspiration pneumonia, placement of an enteral feeding tube should be considered jointly with the patient’s family. When red flags are present for pharyngeal dysfunction (eg cough, wet voice, or recurrent lower respiratory tract infections), the patient should be referred for a Videofluoroscopic Swallowing Study in consultation with a speech–language–feeding therapist.

Other gastrointestinal manifestations of Sanfilippo syndrome include elevations in liver enzymes (alanine aminotransferase ≤ 3.5 times upper limit of normal [ULN]; aspartate aminotransferase ≤ 1.5 × ULN) and hepatomegaly, which do not typically require intervention. Hernias of the umbilicus and inguinal area should be monitored on routine examination and may require intervention if they become problematic.

Cardiac manifestations

In rare cases, cardiac manifestations may require intervention in patients with Sanfilippo syndrome. GAG accumulation can lead to cardiomyopathy, low-grade valve disease and/or dysplastic valves, arrhythmia owing to heparan sulfate accumulation in the conduction system, and other complications that may be problematic in patients surviving to adulthood [ 108 , 109 ]. For example, at least two case studies describe adults with Sanfilippo syndrome types A and C presenting with symptomatic atrioventricular block that required implantation of a pacemaker [ 110 , 111 ].

In a study of 30 patients with Sanfilippo syndrome (n = 16 aged < 18 years), none of the individuals had significant signs or symptoms of cardiac disease, but subclinical systolic and diastolic dysfunction and valvular abnormalities were prevalent, and about 16% had a first-degree atrioventricular block on electrocardiography (ECG) [ 108 ].

All individuals with Sanfilippo syndrome should have baseline cardiac evaluation at diagnosis to include a physical exam, vital signs (eg blood pressure), echocardiogram, and ECG. Thereafter, an echocardiogram is recommended every 24 months if no abnormalities are noted at the initial echocardiogram. If abnormalities are noted on initial or subsequent echocardiograms, the frequency should increase to every 12 months.

A 12-lead ECG and rhythm strip is recommended every 12 months in patients with Sanfilippo syndrome, and as needed owing to the difficulty of assessing symptoms in these patients. If an ECG is abnormal, a Holter monitor should be placed for at least 24–48 h for a more thorough evaluation.

Management of orthopedic complications

Orthopedic complications are a source of discomfort and distress in patients with Sanfilippo syndrome, often involving changes to the hips and spine [ 112 ]. Osteonecrosis of the femoral head and hip dysplasia can be a source of particularly severe discomfort, and intervention should be considered on a case-by-case basis. Complications requiring surgical intervention include progressive scoliosis [ 112 ]. Low bone mass and vitamin D insufficiency or deficiency are prevalent, and patients with decreased mobility or a history of receiving anti-epileptic medication are at risk for osteoporosis and fractures [ 113 ].

Patients with Sanfilippo syndrome should undergo a thorough orthopedic examination at the time of diagnosis. Consensus statements additionally endorse X-ray evaluation of the hips and spine at diagnosis and every 1–2 years from 7 years of age onwards, or sooner if clinically indicated. However, after thoughtful review, the expert clinician steering committee recommends further refinement of this guidance based on accessibility of specialists and procedural risks. It is felt that for patients without overt musculoskeletal symptoms, the initial orthopedic evaluation may be performed by the primary care clinician through a close musculoskeletal exam and a baseline X-ray of the hips and spine. Weighing the risks of cumulative radiation exposure with repeated monitoring X-rays, the steering committee suggests that radiography be performed at the time of diagnosis and then repeated only as clinically indicated. Unless there is clinical suspicion, monitoring for cervical spine instability is not recommended. In addition to the routine musculoskeletal exam, annual visits should also monitor for trigger finger, genu valgus deformity, abnormal spinal curvature, femoral anteversion, and tibial torsion that do not appear to improve or are worsening with age, with referral to an orthopedic specialist as clinically indicated. Given that pain may be difficult to assess and localize in patients with cognitive impairment and behavioral disturbances, radiographic studies of the hips should be considered in the evaluation of otherwise unexplained signs of discomfort or pain.

Facilitating day-to-day activities and maintaining quality of life

Management of pain and distress.

Although the neurological features of Sanfilippo syndrome may be the primary focus of patient care, physical manifestations such as pain and discomfort due to musculoskeletal or gastrointestinal problems can further exacerbate the neurocognitive and behavioral challenges experienced by individuals with this condition [ 9 ]. Thus, after appropriate evaluation for treatable medical complications, management of pain should be a fundamental part of the care of patients with Sanfilippo syndrome, with the aim of improving their quality of life and maintaining mobility. Notably, patients with cognitive impairment may express pain or discomfort via a range of behaviors that are non-classical and individual to them [ 114 ].

There should be a low threshold for investigation of sources of pain in patients with escalating abnormal behaviors or acutely worsening sleep disturbances, or signs of significantly increased agitation. Investigation for sources of pain or discomfort may include consideration of headaches (with consideration of alterations in intracranial pressure or symptoms of normal-pressure hydrocephalus), abdominal discomfort (eg acid reflux, ulcers, intestinal gas pain, and constipation), joint disease (eg arthralgia, arthritis, and osteonecrosis of femoral head), ENT issues (eg otitis and sinusitis), and dental-related pain (Table 4 ). In the case of persistent pain, distress, or agitation for which outpatient evaluation has been unrevealing, admission to hospital for thorough efficient medical workup is recommended. This workup should include hip and spine X-ray; dental examination for signs of decay; abdominal imaging to investigate potential constipation or other obstruction; eye exam with consideration for signs of elevated intracranial or intraocular pressure; complete blood count with differential to check for infection or anemia; measurement of electrolytes; and if other investigations are not conclusive, brain imaging (MRI or computerized tomography) for ventriculomegaly, atrophy, or intracranial bleed is suggested [ 115 ]. It is acknowledged that communicating hydrocephalus (due to defective cerebrospinal fluid reabsorption) is less common in patients with Sanfilippo syndrome than in other MPS disorders and can be difficult to distinguish from brain atrophy in MRI scans [ 116 ]. However, given that patients with GAG accumulation in MPS I and MPS II also have abnormal cerebrospinal fluid reabsorption [ 117 , 118 ], it is reasonable to consider as a potential cause of pain and distress in patients with Sanfilippo syndrome and should be investigated. In the evaluation of increased intracranial pressure, evidence of papilledema may indicate elevated pressure but is not a reliable indicator of chronically elevated intracranial pressure; therefore, a normal fundus does not exclude the presence of intracranial pressure-related symptoms.

Standardized pain assessments appropriate for the patient’s cognitive level and/or caregiver proxy assessments should be included in regular follow-up visits for patients with Sanfilippo syndrome. For patients who have a limited ability to communicate, the revised Non-Communicating Children's Pain Checklist is recommended [ 119 ].

Special education, physical, occupational, speech, and complementary therapy interventions

Patients with Sanfilippo syndrome have unique needs and developmental trajectories that require careful and informed consideration throughout their period of care. Changes in neurocognition, speech, language, and motor skills may be subtle and not obvious from day to day or even month to month. Without careful and consistent monitoring of these outcomes by appropriately trained individuals, which interventions are benefiting a patient and whether alternative approaches need to be adapted are impossible to determine. In this regard, the consistent use of established measurement tools is recommended to track motor skills over time (eg the Peabody Developmental Motor Scales II, the Bayley-III motor domain and the Bruininks–Oseretsky test of motor proficiency, second edition) [ 74 ], with the selection of measures that are most appropriate for the patient [ 120 ].

Whereas for many children who do not have neurodegenerative disorders, goals for receiving supportive interventions are set based on an anticipated improvement in relevant skills, the natural course of Sanfilippo syndrome means that children beyond a certain point in their disease process will instead either lose or never acquire such skills. Therefore, supportive interventions should strive to maintain existing skill levels rather than require improvement in a patient’s abilities for them to qualify for continued access to such services. Similarly, therapeutic goals for rehabilitative therapies such as physical or speech therapy should focus on prolonging skills for as long as possible and improving quality of life and functional access to educational and social environments. Cognitive impairment and the progressive nature of Sanfilippo syndrome should not preclude an affected patient’s access to vision, hearing, behavioral, or any other support services; the patient should be recommended access to these services even after a decline in the relevant skills and abilities.

The provision of an appropriate high-quality, enriching educational environment with regular opportunities for peer engagement helps to ensure maximal developmental gains and skill maintenance [ 9 , 12 , 67 , 71 ]. Consistent routines and structured schedules can have a positive influence on the behavior and quality of life of patients with Sanfilippo syndrome. As much as possible, these patients deserve stimulation and inclusion, even when processes of deterioration have begun. Providing an individual aide in the school setting is helpful and often necessary to maintain the safety of the patient and others in the classroom, as well as to maximize the child's attention, adequately reinforce their attempts to communicate, and support them during educational activities.

Speech regression can contribute to the distress and frustration experienced by the patient and their family, with dysfluencies and speech apraxia as early warning signs of regression in patients with Sanfilippo syndrome [ 11 ]. An array of augmentative and alternative communication (AAC) methods can be used to augment, complement, or replace speech for patients with complex communication needs [ 121 ]. Such methods range from basic tools (eg picture boards and single voice output buttons) to smart devices and dedicated AAC devices that integrate hardware and software to support a patient’s communication needs. The potential benefits of these approaches should be considered on a patient-by-patient basis, noting that patients with Sanfilippo syndrome may require longer and more intensive therapy to achieve success with these methods. The above approaches should be applied to patients with Sanfilippo syndrome as early as possible (ie during maximal cognitive capacity and even prior to loss of verbal speech). AAC methods should be initiated by a trained professional on a trial basis to determine suitability and feasibility, and then generalized for use in home and educational settings as quickly as possible. The type of AAC may need to be adjusted over time per the patient’s need, ability, and level of engagement. Behavioral therapies are helpful in conjunction to increase acceptance and positively reinforce the use of these communication tools.

Regular physical therapy may reduce physical discomfort and support some aspects of mobility in patients with Sanfilippo syndrome, which can have beneficial effects on inattention or other behaviors that may be driven by pain or frustration, as well as bone health, gastrointestinal motility, avoidance of pressure sores, and enabling them to maintain access to their environment. Thus, it is our opinion that physical therapy should be considered as early as possible and be performed regularly prior to, during, and beyond the decline of gross motor skills to maintain mobility and function and reduce development of contractures. The range of motion in the upper and lower extremities should be assessed at diagnosis, on the first visit to any new physical therapy provider, and at least every 6 months. Orthotic bracing may help balance, foot and ankle positioning, and to improve and maintain gait function and mobility for longer.

To help facilitate daily activities for patients with Sanfilippo syndrome, supportive equipment needs should be discussed, and appropriate prescriptions and referrals as needed made every 6 months. A forward-looking, proactive approach is warranted to ensure that required adaptive equipment can be obtained when needed, including a wheelchair or medical stroller, stander, bath seat, activity chair, safety beds, lifts, or specialized car seats. Similarly, adaptations to the home or school environment may be needed owing to the patients’ lack of safety sense and cognitive decline with preserved motor skills.

Although patients with Sanfilippo syndrome are generally of normal weight and height for their gestational age at birth, adults with Sanfilippo syndrome are generally of short stature [ 122 , 123 ]. In a study of 182 patients with Sanfilippo syndrome in Germany, accelerated growth was observed in the first year of life, followed by decelerated growth from 4.5 to 5.0 years of age onwards. On reaching adulthood, these patients were shorter than expected based on the height of their respective parents [ 123 ]. Similarly, growth charts of patients with Sanfilippo syndrome in the Netherlands showed significantly slowed growth from 6 years of age onwards [ 122 ]. Disease-specific growth charts are important tools for tracking growth and recognizing deviation from normal and help physicians to counsel parents regarding growth expectations. Therefore, growth should be monitored and plotted on Sanfilippo syndrome-specific growth curves [ 123 ].

The onset of puberty may be advanced in patients with Sanfilippo syndrome [ 124 , 125 ]. If signs of early puberty are present, referral to a pediatric endocrinologist is warranted. The use of gonadotrophin-releasing hormone agonists is not contraindicated for patients with Sanfilippo syndrome and should be considered in consultation with the patient and their family.

Family support

Coming to terms with a diagnosis of Sanfilippo syndrome—a condition that many people may never have heard of—can be incredibly challenging for family members. Caregivers should be provided with counseling on the natural history of disease progression in the absence of a disease-modifying treatment, both at the time of diagnosis and throughout the disease course. Understanding what the expected symptoms of the disease are can help to ‘normalize’ the patient’s challenging behaviors, sleep, and other concerns during other times of high stress or changing symptom patterns [ 53 , 126 , 127 ]. However, this should not supplant the need to assess for treatable modifiers of symptoms that may improve the quality of life for the patient and their family.

Given that family members living with or caring for an individual with Sanfilippo syndrome will most likely experience significant psychological stress and social challenges, proactive intermittent assessment of caregivers’ anxiety, depression, and chronic traumatic stress with appropriate referral is warranted [ 126 ]. Patient advocacy groups provide a forum for peer-to-peer support and can facilitate the provision of services and financial aid grants available from the government and other community resources. Palliative care teams should be engaged, with regular monitoring of the service needs of the family and patient as these needs vary in intensity and type depending on the age and extent of disease progression.

While there are no approved therapies for patients with Sanfilippo syndrome, disease-specific therapies are being developed and a number of clinical trials have been attempted or are ongoing (eg intravenous and intrathecal enzyme replacement therapy, substrate reduction therapy, autologous stem cell-based lentiviral gene therapy, and adeno-associated viral vector gene therapy). In lieu of the promise provided by these novel therapies, this review aims to distill the best available guidance on how to recognize, diagnose, and care for patients with this devastating, progressive, and life-limiting disease based on the broad consensus of a multidisciplinary panel of expert clinicians from nine countries.

To our knowledge, this is the first example of a consensus guideline for the management of patients with Sanfilippo syndrome. Its development was led by a steering committee consisting of internationally renowned experts in Sanfilippo syndrome. The recommendations described here reflect the current understanding and experience of caring for patients with this condition. While guidelines support consistency in care, clinical judgment should be used to determine if deviation from the described schedule is appropriate based on the patient’s clinical history, extent of organ manifestations, variability of disease phenotype, and in collaboration with the family as to the potential burden of assessments.

It is acknowledged that a potential limitation of these guidelines is the fact that they do not fully encapsulate local variations in terminologies and different cultural systems of care, as some modifications to guideline statements were needed to ensure their applicability across the global healthcare landscape. Furthermore, given the large number of statements required to capture the available published evidence and experience of current clinical practice, not all issues and theories associated with the management of Sanfilippo syndrome could be covered within this review, although a full list of the recommendations that reached consensus are provided in Additional file 1 : Table S2. Some of the statements put forward for consideration did not reach consensus owing to variations in local practice or lack of supporting evidence. For example, consensus was not reached on the appropriateness of routine monitoring of bone density using a dual-energy X-ray absorptiometry scan to assess for fracture risk in patients with prolonged functional immobility. Similarly, routine monitoring for retinal disease via electroretinogram and/or optical coherence in patients who do not have overt visual impairment remains a subject of debate. However, we do not consider that the guidance provided in this document is affected substantially by the omission of these statements. As is common in most rare diseases, some features of the disease are not as well represented in the literature as others. In such areas, there is an increased risk of bias from expert opinion based on clinicians’ individual clinical experience. We attempted to mitigate the impact of this potential bias by including a large number of clinicians with significant experience in Sanfilippo syndrome across a wide range of specialties and geographic locations so that their collective experience would offer a more comprehensive perspective.

Family and patient burden is an important consideration in medical-decision making. The extent of burden that is experienced or anticipated by each patient and family unit is unique. Further, benefits of monitoring procedures may not be immediately evident but rather may be appreciated at a later time point when disease symptoms evolve and the team then has a baseline from which to compare, allowing for better-informed clinical decisions. In this set of guidelines, we aim to respect the autonomy of patients and families by bringing consensus recommendations for proactive care together in one document, thus allowing them to make their own informed, individual decisions regarding benefit–risk–burden calculations in consultation with their care team.

As clinical experience of managing patients with Sanfilippo syndrome continues to grow, along with our understanding of the underlying disease pathways, the strategies described in this review will most likely require updates to reflect the closing of remaining knowledge gaps. The continued study of patients with Sanfilippo syndrome via observational studies, clinical registries, and preclinical studies is essential to ensure that progress continues to be made. Ultimately, the availability of the first disease-specific therapies for Sanfilippo syndrome will result in a major transformation of the clinical landscape and prospects for the patients and families affected by this disorder. The guidance contained here should therefore be reviewed and updated regularly by a panel of appropriately qualified experts.

Conclusions

Sanfilippo syndrome is a complex neurodegenerative disease that, until now, had no published standard global clinical care guideline. This document, created through collaboration between Cure Sanfilippo Foundation (USA) and Sanfilippo Children’s Foundation (Australia), distills 178 guideline statements into an easily digestible document that provides evidence-based, expert-led recommendations. This review is intended to help the provision of consistent care to the patients and families affected by Sanfilippo syndrome, as well as facilitating interventions to improve their quality of life.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

The authors are grateful to Jonathan Morton PhD of Comradis Limited (Oxford, UK) for his assistance in writing this manuscript, funded by Cure Sanfilippo Foundation, and to the many clinicians globally who participated in the online survey to establish consensus.

Funding to support development of these consensus guidelines was provided in part by Global Genes, BioMarin Pharmaceutical Inc, Cure Sanfilippo Foundation, and Sanfilippo Children’s Foundation. Global Genes and BioMarin were not involved in any stages of the process and did not influence the design or content of the resulting guidance statements or manuscript .

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Nicole Muschol

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University of Manchester, Manchester, UK

Simon A. Jones

University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

Joseph Muenzer

Department of Neurology and Clinical Neurophysiology, Women’s and Children’s Health Network and the Discipline of Paediatrics, University of Adelaide, Adelaide, Australia

Nicholas J. C. Smith

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Chester B. Whitley

Sanfilippo Children’s Foundation, Freshwater, NSW, Australia

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MD and CO’N devised the project and the main conceptual ideas and were in charge of overall direction and planning. KE performed the literature review and devised, distributed, and analyzed the survey. CO’N revised guideline statements and ED, LM, and KE provided administrative and technical support. CO’N, MD, and ED additionally provided the caregiver perspective. RG, SAJ, JM, NM, NJCS, and CBW were members of the steering committee who guided the direction of the project. They recommended members for the Guideline Development Group, reviewed guideline statements, and identified and filled gaps in recommendations. CO’N and NM took the lead in writing the manuscript with help from JM. All authors provided critical feedback and helped shape the research, analysis, and manuscript.

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Nicole Muschol, Roberto Giugliani, Joseph Muenzer, Chester B. Whitley, Nicholas J. C. Smith, and Simon A. Jones have no competing interests in relation to this manuscript. Megan Donnell is on the Board of Sanfilippo Children's Foundation and has no competing interests in relation to this manuscript. Kristina Elvidge and Lisa Melton are employees of Sanfilippo Children’s Foundation and have no competing interests in relation to this manuscript. Cara O’Neill is an employee of Cure Sanfilippo Foundation and has no competing interests in relation to this manuscript. Elise Drake is a volunteer of Cure Sanfilippo Foundation and has no competing interests in relation to this manuscript.

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Muschol, N., Giugliani, R., Jones, S.A. et al. Sanfilippo syndrome: consensus guidelines for clinical care. Orphanet J Rare Dis 17 , 391 (2022). https://doi.org/10.1186/s13023-022-02484-6

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Clinical care review systems in healthcare: a systematic review

Laura e. walker.

1 Department of Emergency Medicine and Health Sciences Research, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 USA

David M. Nestler

Torrey a. laack, casey m. clements, patricia j. erwin.

2 Mayo Clinic Libraries and Health Sciences Research, Mayo Clinic, Rochester, MN USA

Lori Scanlan-Hanson

M. fernanda bellolio, associated data.

Clinical care review is the process of retrospectively examining potential errors or gaps in medical care, aiming for future practice improvement. The objective of our systematic review is to identify the current state of care review reported in peer-reviewed publications and to identify domains that contribute to successful systems of care review.

A librarian designed and conducted a comprehensive literature search of eight electronic databases. We evaluated publications from January 1, 2000, through May 31, 2016, and identified common domains for care review. Sixteen domains were identified for further abstraction.

We found that there were few publications that described a comprehensive care review system and more focus on individual pathways within the overall systems. There is inconsistent inclusion of the identified domains of care review.

While guidelines for some aspects of care review exist and have gained traction, there is no comprehensive standardized process for care review with widespread implementation.

Electronic supplementary material

The online version of this article (10.1186/s12245-018-0166-y) contains supplementary material, which is available to authorized users.

Clinical care review is the process of retrospectively examining potential errors or gaps in medical care, with a goal of future practice improvement. This goes by many different names, sometimes with different audiences or case types, including peer review, adverse event review, sentinel event review, and root cause analysis. The concept of care review is widely accepted and encouraged among safety and quality healthcare leaders. However, a paucity of literature exists discussing and describing the current state of clinical care review.

The challenges and risks of contemporary medical care are well described. Medical error and its resulting outcomes have been defined and measured in many different ways, leading to varying quantifications of the effects [ 1 ]. The Institute of Medicine’s (IOM) 1999 report entitled “To Err is Human” [ 2 ] estimated that as many as 44,000 to 98,000 deaths annually in the USA occur as a result of medical error. Publication of “To Err is Human” was a landmark event in the recognition of the role of adverse events in medical care in the USA. This represents a shift in the focus on adverse events to look toward systems issues as a cause or error and a call to identify and act to prevent medical error. The National Quality Foundation estimates that, in 2010, medical errors affected 15.5% of Medicare beneficiaries, with nearly half of these errors considered preventable [ 3 ]. More recently, Makary and Daniel estimated that as many as 250,000 deaths per year in the USA are due to medical error, making it the third leading cause of death by their estimation [ 1 ]. Review of adverse events allows for investigation into, and classification of the causes of, the event and presents an opportunity to modify systems and behaviors to prevent future similar errors. As a part of the strategic approach for increasing safety, the IOM’s “To Err is Human” recommended “Identifying and learning from errors by ... encouraging health care organizations and practitioners to develop and participate in voluntary reporting systems.” They went on to say “Such systems can focus on a much broader set of errors, mainly those that do no or minimal harm, and help detect system weaknesses that can be fixed before the occurrence of serious harm, thereby providing rich information to health care organizations in support of their quality improvement efforts” [ 1 ].

Given the long standing call for clinical care review, with limited literature to inform care review systems, we conducted a qualitative systematic review to identify characteristics discussed in existing models for care review. The objectives are to (1) describe the current state of care review and (2) identify elements from published care review systems that contribute to their success. This systematic review will allow for a more complete evaluation of the current state of clinical care review and will identify areas for future scholarly activity.

This is a qualitative systematic review of studies describing and evaluating care review systems. This study was exempt from our IRB review. This report adheres to the recommendations made in the preferred reporting items for systematic reviews (PRISMA) statement [ 4 ]. A protocol was written before the beginning of the investigation.

We included original research studies with any methodological design including cohort studies, case controls, and randomized trials, as well as commentaries, narrative reviews, letters to the editor, and abstracts in peer-reviewed journals that reported models for care review. Search results were limited to publications after January 1, 2000, to focus on publications since the release of “To Err is Human” [ 1 ]—a turning point in the way adverse events are analyzed and regarded. In choosing relevant publications, some articles described their process as the main purpose of the article, while others incidentally described a care review process, while instead focusing on a specific intervention or aspect of their mechanism for review. Either was acceptable, as they both shed light on a review system for analysis.

All types of patients and hospital settings were included, as well as recommendations from professional organizations and companies. This study’s investigators are physicians with involvement in quality improvement, adverse event identification and management, patient safety, and leadership of committees for clinical care review.

A senior expert librarian (P.E.) designed and conducted a comprehensive search of eight electronic databases, including Ovid MEDLINE, Ovid EMBASE, EBSCO CINAHL, Ovid CENTRAL, Ovid Cochrane Database of Systematic Reviews, Web of Science, and Scopus. Our search was done on June 10, 2016, and includes publications from January 1, 2000, through May 31, 2016. We included published conference abstracts in our search. There was no language restriction to the search strategy. Bibliography and reference lists of the articles obtained through database search were reviewed to identify additional publications for inclusion. The search strategy can be found in the Additional file  1 .

Qualitative assessment and data abstraction process

Two investigators (L.W. and D.N.) identified common domains in the initial literature review to determine which data to abstract, and included additional variables determined to be clinically important based on their experience in the clinical care review process and practice improvement. Domains included were description of systems improvement, educational output and feedback, description of a standardized process and referral mechanism, consideration of the case outcome, deliverables of the review system including non-punitive process and recognition of excellence, multidisciplinary involvement, dedicated process leadership, reviewer training, case blinding/anonymity, and implementation of improvement recommendations by the investigating group. These are further described in Table  1 .

Descriptions of the 16 domains of care review

In phase I of the review, one investigator (L.W.) independently screened all titles yielded by the initial search strategy for possible inclusion. After identifying appropriateness for possible inclusion, phase II consisted of two reviewers (L.W. and D.N.) independently evaluating the abstracts of publications identified in phase I. The publications from phase II were then retrieved in full text and assessed for inclusion of domain abstraction in phase III by two independent reviewers. The agreed-upon articles were assessed by independent reviewers in duplicate, to abstract the identified domains of care review in phase III.

In phase II, disagreement between reviewers was reconciled by discussion and consensus. The investigators were not blinded to the authors, journals, or results of studies. In phase III, disagreements on the data abstraction were resolved by a third independent reviewer who assessed the article and determined if the theme was included in the care review process. Descriptions of the 16 domains were supplied to all reviewers prior to data abstraction for reference.

Critical appraisal is the process of systematically examining research evidence to assess its validity, results, and relevance before using it to inform a decision. Instruments developed to support quality appraisal usually share some basic criteria for the assessment of qualitative research. These include the need for research to have been conducted ethically, the consideration of relevance to inform practice or policy, the use of appropriate and rigorous methods, and the clarity, coherence of reporting, address of reliability, validity, and objectivity [ 5 ].

In considering the most appropriate instruments to use for critical appraisal, we considered using the Cochrane Collaboration Bias Appraisal Tool [ 6 ] and a modified Newcastle-Ottawa Scale tool [ 7 ]. The nature of our qualitative data abstraction precluded the use of these tools. While the studies we evaluated may have included randomized controlled trials and been at risk for bias, the results of the publications evaluated were not typically relevant to our goal of qualitative domain abstraction. Many publications we evaluated were narrative in nature—describing a process without presentation of data, either qualitative or quantitative. For those publications that did present data relevant to our domains, the effect of bias within the study was felt to be unlikely to impact our qualitative data collection because the abstracted domains—descriptions of processes—were not affected by the results of the studies. We reviewed the items described in the Standards for Reporting Qualitative Research (SRQR) [ 8 ] and the Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) [ 9 ] statement. The SRQR and ENTREQ aim to improve the transparency of all aspects of qualitative research by providing clear standards for reporting qualitative research. When assessing the risk of bias, we decided not to exclude articles based on their quality assessment. All potentially valuable insights were included. From each study, we extracted the domains relevant to care review processes. We tabulated the results and created graphics based on frequencies. No quantitative data was appropriate for abstraction, so we did not perform a meta-analysis.

The initial library search strategy identified 1318 titles for review. In phase I, 440 abstracts were reviewed, 76 of which were selected for full-text review in phase II. Fifteen articles from outside sources and bibliography review were also identified and reviewed. In total, 91 full-text articles were assessed, and after reconciliation between two independent reviewers, 47 articles were initially found to be appropriate for inclusion in our analysis of the domains of care review. One article was removed in the abstraction process, as both reviewers independently determined that it did not meet inclusion criteria [ 10 ] leading to 46 unique articles reviewed.

Domains were abstracted by two independent reviewers for each of the 46 articles in phase III. Articles that described a care review process from the same institution were consolidated to reflect the most complete view of that process possible, as aspects may have been reported differently in multiple articles/abstracts. Figure  1 shows the study selection process. Ultimately, we evaluated the care review systems from 35 unique institutions.

Study selection process

Study characteristics

Among the 46 studies, 35 represented unique institutions and 11 were same authors/institutions describing different aspects of the process or domains. The types of articles identified included 14 descriptive [ 11 – 24 ], three editorials [ 25 – 27 ] 15 prospective [ 28 – 42 ], seven quality improvement projects [ 12 , 43 – 48 ], and ten retrospective [ 11 , 30 , 49 – 56 ]. The 16 domains of successful care review that were identified for abstraction are presented and defined in Table  1 .

The percentage of frequency of each component is shown in Fig.  2 . The most commonly identified component of a care review process was utilizing an analysis of systems issues contributing to the case (32 institutions, 91.4%), followed by utilizing a standardized process for case review (30 institutions, 85.7%) and use of a structured case classification system (28 institutions, 80.0%). The least common components identified were recognition of excellence and use of case blinding/anonymity in reviews (5 institutions, 14.3%). Some articles were consistent with more than one article type and were classified as both.

Frequency of domain identification

Table  2 shows the distribution of all components in the full-text articles reviewed, with consolidation of same-institutions. No article/institution identified all 16 items evaluated by reviewers. Two institutions identified 14 of 16 items: Lehigh Valley and Johns Hopkins.

Distribution of care review domains

Our systematic review shows that, in the first two decades since the IOM report calling for improved safety systems, there have been few articles outlining a comprehensive clinical care review process. Additionally, most articles discuss their care review systems in the context of describing an aspect of their process, or corresponding improvement initiative.

Systems analysis—defined as the assessment of the effects of external forces such as policies, workflows, and software such as the electronic medical record on the critical event—was the most commonly identified care review process characteristic. Many identified articles describe the importance of evaluating how a person works within a system, rather than in isolation, to identify improvement opportunities. Assuming individuals are properly motivated with benign intent, looking at the system surrounding, the care avoids an antagonistic approach and supports the IOM’s underlying reasons for calling for care review processes—to prevent future errors.

Similarly, standardized processes and structured case classification were frequently discussed in the literature. To meet the IOM’s recommendations for creating care review “systems,” having a standardized process that uses structured classification is likely necessary. Without standardization, reviews would likely be sporadic, inefficient, and challenging to implement and subsequently inform future practice. Without structured classification, one could assume that conclusions would also be difficult to interpret.

Although some of these characteristics were common among reported care review systems, others are only rarely reported. Recognition of excellence and blinding of cases were reported in just five (14%) of the reports. Institutions that recognize excellence while performing care reviews were supportive of the practice, and one can understand why this would support the culture needed to have an effective care review system, and perhaps designers of future care review systems may wish to consider implementing this component. Similarly, anonymous review, or blinding, is intended to reduce bias and may allow a more objective review of each case. However, its infrequent mention may be indicative of unpublished prior experiences that may have supported avoiding this practice. From our experience, these are controversial topics, and future work is needed to understand the effects of specific characteristics on the overall care review process.

One additional characteristic that review processes must be supported by a functioning organizational system should receive particular attention. Although this was specifically identified by only 19 organizations, the downstream benefit to reviewing an episode of care and making recommendations for change in a non-functional system is likely lost. Key stakeholders in the process (physicians, nurse practitioners, physician assistants, nursing staff, support staff, etc.) are seemingly necessary for the care review process, and the administrative and leadership structure must be supportive of recommendations for change after care review is completed. This combination is strongly conducive to a process that engenders trust from the care team, which in turn bolsters the system as cases are referred for review, and staff engage in further problem solving.

Limitations

The articles evaluated come from a variety of settings—from consulting firms to in situ care review systems. Some authors strove to describe a comprehensive local practice, while others focused primarily on a particular component of a larger system. This heterogeneity limits the generalizability as the variability from one system to another may indicate institution- or system-specific adaptations to facilitate the process. A solution for one setting may not represent a good solution for another. We included articles from institutions and consulting firms describing or self-reporting care review systems, and it is not possible to know the true effectiveness of the processes described when removed from clinical context. It may be that there is an over-emphasis on some areas of care review believed to be ideal that are not practiced as described, and also possible that not all aspects of a process are represented. Particularly in the articles that discuss the care review process as the context for a specific project, it is possible that not all the details on the over-arching system of care review in place are described resulting in abstraction of domains in what is an incomplete description.

The domains we used during abstraction were determined by screening the included articles and supplemented by expert opinion. It is possible that there are additional variables that are more important, but less common, and were not included in our analysis. It is possible that a care review process we reviewed may include some of the 16 characteristics but did not specifically mention them in the articles reviewed. Additionally, the qualitative nature of the abstraction and interpretation of each item definitions are complex and may lead to less reliable results.

In an effort to reduce the effects of bias and definition complexity, all articles were reviewed in duplicate—both for inclusion in the study as well as abstraction of data. Disagreements were resolved by discussion and consensus for article inclusion and adjudicated by a third reviewer for the domain abstraction.

Despite increased discussion among institutions such as IOM and the National Patient Safety Foundation, in the last 16 years, there have been relatively few publications describing clinical care review processes and no clear evidence of a cultural shift to embrace clinical care review in an organized fashion. We have identified 16 domains of focus in a care review process and found that the approach to care review is highly variable as represented in the literature.

Future research

The effects of different aspects of care review processes have not been well studied. This presents an opportunity to evaluate processes that are present in many hospitals and health systems and identify truly effective, rather than simply common, practices, as identified within.

Additional file

Search strategy. (DOCX 14 kb)

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors’ contributions

All the authors have contributed substantially to this manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

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