Diabetes mellitus is associated with 90-day mortality in old critically ill COVID-19 patients: a multicenter prospective observational cohort study.

BACKGROUND: Several studies have found an association between diabetes mellitus, disease severity and outcome in COVID-19 patients. Old critically ill patients are particularly at risk. This study aimed to investigate the impact of diabetes mellitus on 90-day mortality in a high-risk cohort of critically ill patients over 70 years of age. METHODS: This multicentre international prospective cohort study was performed in 151 ICUs across 26 countries. We included patients ≥ 70 years of age with a confirmed SARS-CoV-2 infection admitted to the intensive care unit from 19th March 2020 through 15th July 2021. Patients were categorized into two groups according to the presence of diabetes mellitus. Primary outcome was 90-day mortality. Kaplan-Meier overall survival curves until day 90 were analysed and compared using the log-rank test. Mixed-effect Weibull regression models were computed to investigate the influence of diabetes mellitus on 90-day mortality. RESULTS: This study included 3420 patients with a median age of 76 years were included. Among these, 37.3% (n = 1277) had a history of diabetes mellitus. Patients with diabetes showed higher rates of frailty (32% vs. 18%) and several comorbidities including chronic heart failure (20% vs. 11%), hypertension (79% vs. 59%) and chronic kidney disease (25% vs. 11%), but not of pulmonary comorbidities (22% vs. 22%). The 90-day mortality was significantly higher in patients with diabetes than those without diabetes (64% vs. 56%, p < 0.001). The association of diabetes and 90-day mortality remained significant (HR 1.18 [1.06-1.31], p = 0.003) after adjustment for age, sex, SOFA-score and other comorbidities in a Weibull regression analysis. CONCLUSION: Diabetes mellitus was a relevant risk factor for 90-day mortality in old critically ill patients with COVID-19. STUDY REGISTRATION: NCT04321265, registered March 19th, 2020.

Contribution of information about acute and geriatric characteristics to decisions about life-sustaining treatment for old patients in intensive care.

BACKGROUND: Life-sustaining treatment (LST) in the intensive care unit (ICU) is withheld or withdrawn when there is no reasonable expectation of beneficial outcome. This is especially relevant in old patients where further functional decline might be detrimental for the self-perceived quality of life. However, there still is substantial uncertainty involved in decisions about LST. We used the framework of information theory to assess that uncertainty by measuring information processed during decision-making. METHODS: Datasets from two multicentre studies (VIP1, VIP2) with a total of 7488 ICU patients aged 80 years or older were analysed concerning the contribution of information about the acute illness, age, gender, frailty and other geriatric characteristics to decisions about LST. The role of these characteristics in the decision-making process was quantified by the entropy of likelihood distributions and the Kullback-Leibler divergence with regard to withholding or withdrawing decisions. RESULTS: Decisions to withhold or withdraw LST were made in 2186 and 1110 patients, respectively. Both in VIP1 and VIP2, information about the acute illness had the lowest entropy and largest Kullback-Leibler divergence with respect to decisions about withdrawing LST. Age, gender and geriatric characteristics contributed to that decision only to a smaller degree. CONCLUSIONS: Information about the severity of the acute illness and, thereby, short-term prognosis dominated decisions about LST in old ICU patients. The smaller contribution of geriatric features suggests persistent uncertainty about the importance of functional outcome. There still remains a gap to fully explain decision-making about LST and further research involving contextual information is required. TRIAL REGISTRATION: VIP1 study: NCT03134807 (1 May 2017), VIP2 study: NCT03370692 (12 December 2017).

Prognostication in Very Old Intensive Care Patients with Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is a risk factor for morbidity and mortality during critical illness especially in very old patients admitted to intensive care units. OBJECTIVES: To identify prognostic markers for AKI patients. METHODS: This single-center retrospective study was based on a patient registry of a medical intensive care unit. Hospital records of patients aged 80 years or older admitted between 2005 and 2015 were examined. Patients who developed AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines within 4 days of admission were included in this study. RESULTS: The study comprised 96 patients with AKI and 81 age- and sex-matched controls without AKI. Mean acute physiology and chronic health evaluation (APACHE) II score was 30 with an ICU mortality of 27% in very old patients with AKI. The odds ratio of hospital mortality for these patients was 5.02 compared to controls (49% vs. 16%). APACHE II score and fluid balance in the first 2 days of ICU admission were the strongest predictors of ICU mortality with an area under the receiver operating characteristic of 0.76. Of the 47 patients with AKI who survived hospital admission, 30 were discharged home. CONCLUSIONS: Mortality was increased in very old ICU patients with AKI. Among survivors, two-thirds returned home.

Noninvasive ventilation in COVID-19 patients aged ≥ 70 years-a prospective multicentre cohort study.

BACKGROUND: Noninvasive ventilation (NIV) is a promising alternative to invasive mechanical ventilation (IMV) with a particular importance amidst the shortage of intensive care unit (ICU) beds during the COVID-19 pandemic. We aimed to evaluate the use of NIV in Europe and factors associated with outcomes of patients treated with NIV. METHODS: This is a substudy of COVIP study-an international prospective observational study enrolling patients aged ≥ 70 years with confirmed COVID-19 treated in ICU. We enrolled patients in 156 ICUs across 15 European countries between March 2020 and April 2021.The primary endpoint was 30-day mortality. RESULTS: Cohort included 3074 patients, most of whom were male (2197/3074, 71.4%) at the mean age of 75.7 years (SD 4.6). NIV frequency was 25.7% and varied from 1.1 to 62.0% between participating countries. Primary NIV failure, defined as need for endotracheal intubation or death within 30 days since ICU admission, occurred in 470/629 (74.7%) of patients. Factors associated with increased NIV failure risk were higher Sequential Organ Failure Assessment (SOFA) score (OR 3.73, 95% CI 2.36-5.90) and Clinical Frailty Scale (CFS) on admission (OR 1.46, 95% CI 1.06-2.00). Patients initially treated with NIV (n = 630) lived for 1.36 fewer days (95% CI - 2.27 to - 0.46 days) compared to primary IMV group (n = 1876). CONCLUSIONS: Frequency of NIV use varies across European countries. Higher severity of illness and more severe frailty were associated with a risk of NIV failure among critically ill older adults with COVID-19. Primary IMV was associated with better outcomes than primary NIV. Clinical Trial Registration NCT04321265 , registered 19 March 2020, https://clinicaltrials.gov .

Association between tracheostomy timing and outcomes for older critically ill COVID-19 patients: prospective observational study in European intensive care units.

BACKGROUND: Tracheostomy is performed in patients expected to require prolonged mechanical ventilation, but to date optimal timing of tracheostomy has not been established. The evidence concerning tracheostomy in COVID-19 patients is particularly scarce. We aimed to describe the relationship between early tracheostomy (≤10 days since intubation) and outcomes for patients with COVID-19. METHODS: This was a prospective cohort study performed in 152 centres across 16 European countries from February to December 2020. We included patients aged ≥70 yr with confirmed COVID-19 infection admitted to an intensive care unit, requiring invasive mechanical ventilation. Multivariable analyses were performed to evaluate the association between early tracheostomy and clinical outcomes including 3-month mortality, intensive care length of stay, and duration of mechanical ventilation. RESULTS: The final analysis included 1740 patients with a mean age of 74 yr. Tracheostomy was performed in 461 (26.5%) patients. The tracheostomy rate varied across countries, from 8.3% to 52.9%. Early tracheostomy was performed in 135 (29.3%) patients. There was no difference in 3-month mortality between early and late tracheostomy in either our primary analysis (hazard ratio [HR]=0.96; 95% confidence interval [CI], 0.70-1.33) or a secondary landmark analysis (HR=0.78; 95% CI, 0.57-1.06). CONCLUSIONS: There is a wide variation across Europe in the timing of tracheostomy for critically ill patients with COVID-19. However, we found no evidence that early tracheostomy is associated with any effect on survival amongst older critically ill patients with COVID-19. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT04321265.

Prognosis of Chronically Ventilated Patients in a Long-Term Ventilation Facility: Association with Age, Consciousness and Cognitive State.

Background: The number of adults requiring prolonged mechanical ventilation (PMV) including those with cognitive impairment or disorders of consciousness is escalating. We aimed to compare in a long-term acute care hospital (LTACH) mortality and length of stay (LOS) among three age groups (40-59y, 60-79y, ≥80y) of hospitalized PMV patients, and according to consciousness and cognitive state at admission. Methods: We obtained data from the health records of 308 adults aged ≥40 years requiring PMV hospitalized at a Chronic Ventilator Dependent Unit in a LTACH between 01/01/2015 to 06/30/2019 and followed-up until discharge or death or until 12/31/2019. Results: At admission to LTACH, 42.2% of PMV patients were in a vegetative state/ minimally conscious state (VS/MCS); 32.5% were severely cognitively impaired, 11.0% were mildly to moderately cognitively impaired, 12.3% had no cognitive impairment, and 1.9% had intellectual disability/psychiatric disorder. In-LTACH LOS (months) decreased from 34.6 ± 42.6 at age 40-59y, 19.1 ± 22.3 at 60-79y to 14.4 ± 19.3 at age ≥80y (p = .006). In-LTACH mortality was 30.6% for 40-59y, 41.1% for 60-79y and 54.8% for age ≥80y. In-LTACH LOS (months) was 23.8 ± 30.7 for VS/MCS, 15.1 ± 19.5 for the severely cognitively impaired, 10.0 ± 12.8 for mild to moderate cognitive impairment and 18.9 ± 21.9 for those without cognitive impairment (p = .02). In-LTACH mortality was 50.8% for VS/MCS, 58.0% for the severely cognitively impaired, 26.5% for mild to moderate cognitive impairment and 13.2% for those without cognitive impairment (p < .001). Conclusion: In this population requiring PMV, mortality and in-LTACH LOS worsened with age. In-LTACH LOS was longest for VS/MCS patients, who had a mean survival of about two years, followed by those without cognitive impairment and then those with severe cognitive impairment. Mortality was associated with worse consciousness and cognitive state. These findings highlight the importance of discussing end-of-life decisions with patients and family members regarding resuscitation/intubation and the long-term management of these patients.

Health-related quality of life in older patients surviving ICU treatment for COVID-19: results from an international observational study of patients older than 70 years.

BACKGROUND: health-related quality of life (HRQoL) is an important patient-centred outcome in patients surviving ICU admission for COVID-19. It is currently not clear which domains of the HRQoL are most affected. OBJECTIVE: to quantify HRQoL in order to identify areas of interventions. DESIGN: prospective observation study. SETTING: admissions to European ICUs between March 2020 and February 2021. SUBJECTS: patients aged 70 years or older admitted with COVID-19 disease. METHODS: collected determinants include SOFA-score, Clinical Frailty Scale (CFS), number and timing of ICU procedures and limitation of care, Katz Activities of Daily Living (ADL) dependence score. HRQoL was assessed at 3 months after ICU admission with the Euro-QoL-5D-5L questionnaire. An outcome of ≥4 on any of Euro-QoL-5D-5L domains was considered unfavourable. RESULTS: in total 3,140 patients from 14 European countries were included in this study. Three months after inclusion, 1,224 patients (39.0%) were alive and the EQ-5D-5L from was obtained. The CFS was associated with an increased odds ratio for an unfavourable HRQoL outcome after 3 months; OR 1.15 (95% confidence interval (CI): 0.71-1.87) for CFS 2 to OR 4.33 (95% CI: 1.57-11.9) for CFS ≧ 7. The Katz ADL was not statistically significantly associated with HRQoL after 3 months. CONCLUSIONS: in critically ill old intensive care patients suffering from COVID-19, the CFS is associated with the subjectively perceived quality of life. The CFS on admission can be used to inform patients and relatives on the risk of an unfavourable qualitative outcome if such patients survive.

Who gets the ventilator? A multicentre survey of intensivists' opinions of triage during the first wave of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has caused a shortage of intensive care resources. Intensivists' opinion of triage and ventilator allocation during the COVID-19 pandemic is not well described. METHODS: This was a survey concerning patient numbers, bed capacity, triage guidelines, and three virtual cases involving ventilator allocations. Physicians from 400 ICUs in a research network were invited to participate. Preferences were assessed with a five-point Likert scale. Additionally, age, gender, work experience, geography, and religion were recorded. RESULTS: Of 437 responders 31% were female. The mean age was 44.4 (SD 11.1) with a mean ICU experience of 13.7 (SD 10.5) years. Respondents were mostly European (88%). Sixty-six percent had triage guidelines available. Younger patients and caretakers of children were favoured for ventilator allocation although this was less clear if this involved withdrawal of the ventilator from another patient. Decisions did not differ with ICU experience, gender, religion, or guideline availability. Consultation of colleagues or an ethical committee decreased with age and male gender. CONCLUSION: Intensivists appeared to prioritise younger patients for ventilator allocation. The tendency to consult colleagues about triage decreased with age and male gender. Many found such tasks to be not purely medical and that authorities should assume responsibility for triage during resource scarcity.

Assessing the fear of COVID-19 scale among health care workers in Israel: a psychometric validation study.

We explored the psychometric properties of the Hebrew version of the Fear of COVID-19 (FCV-19S) scale among health care workers in a large medical center in Israel. Participants (N = 705) completed the FCV-19S scale, as well as resilience, subjective well-being, and meaning in life using validated scales. Results showed a two-factor structural model accounting for 79.33% of the total variance. Both factors were negatively associated with resilience and satisfaction with life. Results suggest the FCV-19S has good psychometric properties among health care workers and may be used to assess the effects of the pandemic in this population.

The management of multi-morbidity in elderly patients: Ready yet for precision medicine in intensive care?

There is ongoing demographic ageing and increasing longevity of the population, with previously devastating and often-fatal diseases now transformed into chronic conditions. This is turning multi-morbidity into a major challenge in the world of critical care. After many years of research and innovation, mainly in geriatric care, the concept of multi-morbidity now requires fine-tuning to support decision-making for patients along their whole trajectory in healthcare, including in the intensive care unit (ICU). This article will discuss current challenges and present approaches to adapt critical care services to the needs of these patients.

Differences in mortality in critically ill elderly patients during the second COVID-19 surge in Europe.

BACKGROUND: The primary aim of this study was to assess the outcome of elderly intensive care unit (ICU) patients treated during the spring and autumn COVID-19 surges in Europe. METHODS: This was a prospective European observational study (the COVIP study) in ICU patients aged 70 years and older admitted with COVID-19 disease from March to December 2020 to 159 ICUs in 14 European countries. An electronic database was used to register a number of parameters including: SOFA score, Clinical Frailty Scale, co-morbidities, usual ICU procedures and survival at 90 days. The study was registered at ClinicalTrials.gov (NCT04321265). RESULTS: In total, 2625 patients were included, 1327 from the first and 1298 from the second surge. Median age was 74 and 75 years in surge 1 and 2, respectively. SOFA score was higher in the first surge (median 6 versus 5, p < 0.0001). The PaO2/FiO2 ratio at admission was higher during surge 1, and more patients received invasive mechanical ventilation (78% versus 68%, p < 0.0001). During the first 15 days of treatment, survival was similar during the first and the second surge. Survival was lower in the second surge after day 15 and differed after 30 days (57% vs 50%) as well as after 90 days (51% vs 40%). CONCLUSION: An unexpected, but significant, decrease in 30-day and 90-day survival was observed during the second surge in our cohort of elderly ICU patients. The reason for this is unclear. Our main concern is whether the widespread changes in practice and treatment of COVID-19 between the two surges have contributed to this increased mortality in elderly patients. Further studies are urgently warranted to provide more evidence for current practice in elderly patients. TRIAL REGISTRATION NUMBER: NCT04321265 , registered March 19th, 2020.

The impact of frailty on survival in elderly intensive care patients with COVID-19: the COVIP study.

BACKGROUND: The COVID-19 pandemic has led highly developed healthcare systems to the brink of collapse due to the large numbers of patients being admitted into hospitals. One of the potential prognostic indicators in patients with COVID-19 is frailty. The degree of frailty could be used to assist both the triage into intensive care, and decisions regarding treatment limitations. Our study sought to determine the interaction of frailty and age in elderly COVID-19 ICU patients. METHODS: A prospective multicentre study of COVID-19 patients ≥ 70 years admitted to intensive care in 138 ICUs from 28 countries was conducted. The primary endpoint was 30-day mortality. Frailty was assessed using the clinical frailty scale. Additionally, comorbidities, management strategies and treatment limitations were recorded. RESULTS: The study included 1346 patients (28% female) with a median age of 75 years (IQR 72-78, range 70-96), 16.3% were older than 80 years, and 21% of the patients were frail. The overall survival at 30 days was 59% (95% CI 56-62), with 66% (63-69) in fit, 53% (47-61) in vulnerable and 41% (35-47) in frail patients (p < 0.001). In frail patients, there was no difference in 30-day survival between different age categories. Frailty was linked to an increased use of treatment limitations and less use of mechanical ventilation. In a model controlling for age, disease severity, sex, treatment limitations and comorbidities, frailty was independently associated with lower survival. CONCLUSION: Frailty provides relevant prognostic information in elderly COVID-19 patients in addition to age and comorbidities. Trial registration Clinicaltrials.gov: NCT04321265 , registered 19 March 2020.

Relationship between the Clinical Frailty Scale and short-term mortality in patients ≥ 80 years old acutely admitted to the ICU: a prospective cohort study.

BACKGROUND: The Clinical Frailty Scale (CFS) is frequently used to measure frailty in critically ill adults. There is wide variation in the approach to analysing the relationship between the CFS score and mortality after admission to the ICU. This study aimed to evaluate the influence of modelling approach on the association between the CFS score and short-term mortality and quantify the prognostic value of frailty in this context. METHODS: We analysed data from two multicentre prospective cohort studies which enrolled intensive care unit patients ≥ 80 years old in 26 countries. The primary outcome was mortality within 30-days from admission to the ICU. Logistic regression models for both ICU and 30-day mortality included the CFS score as either a categorical, continuous or dichotomous variable and were adjusted for patient's age, sex, reason for admission to the ICU, and admission Sequential Organ Failure Assessment score. RESULTS: The median age in the sample of 7487 consecutive patients was 84 years (IQR 81-87). The highest fraction of new prognostic information from frailty in the context of 30-day mortality was observed when the CFS score was treated as either a categorical variable using all original levels of frailty or a nonlinear continuous variable and was equal to 9% using these modelling approaches (p < 0.001). The relationship between the CFS score and mortality was nonlinear (p < 0.01). CONCLUSION: Knowledge about a patient's frailty status adds a substantial amount of new prognostic information at the moment of admission to the ICU. Arbitrary simplification of the CFS score into fewer groups than originally intended leads to a loss of information and should be avoided. Trial registration NCT03134807 (VIP1), NCT03370692 (VIP2).

Longitudinal patterns of cytokine expression at the individual level in humans after laparoscopic sleeve gastrectomy.

The study of the human response to injury has been hampered by the inherent heterogeneity in the models and methods used. By studying a standard injury longitudinally, using individual patient-level analysis, we endeavoured to better describe its dynamics. We analysed clinical variables, clinical laboratory and plasma cytokines from 20 patients at five time points. Clustering analysis showed two prototype patterns of cytokine behaviour: a concordant type, where cytokines behave the same way for all patients (notably IL-0 and TNFα), and a variable type, where different patterns of expression are seen for different patients (notably IL-8, IL-6 and IL-1RA). Analysis of the cytokines at the individual patient-level showed a strong four-way correlation between IL-1RA, GCSF, MIP-1ß and MCP-1. As it holds for most patients and not just on average, this suggests that they form a network which may play a central role in the response to gastro-intestinal injuries in humans. In conclusion, the longitudinal analysis of cytokines in a standard model allowed the identification of their underlying patterns of expression. We propose that the two prototype patterns shown may reflect the mechanism that separates the common and individual aspects of the injury response.

Comparison of Patients Undergoing Tracheostomy in the Intensive Care Unit versus in the Wards.

BACKGROUND: In Israel, critically ill patients are ventilated and managed in intensive care units or general wards. OBJECTIVES: To compare the mortality rates and long-term cognitive and functional outcomes of ventilated patients who underwent tracheostomy insertion in the Medical ICU (MICU) versus those cared for in the in-patient wards. METHODS: The study comprised 170 patients who underwent percutaneous dilatational tracheostomy (PDT) over an 18-month period in the MICU (n=102) and in in-patient wards (internal medicine and neurology) (n=68). Telephone interviews were conducted with living patients and/or their relatives at least 6 months after discharge from the hospital. RESULTS: Ward patients were 10 years older than ICU patients undergoing PDT (P = 0.003). The length of stay (LOS) in the wards was longer than in the ICU (P < 0.001), whereas the total LOS in the hospital was similar (P = 0.43). ICU mortality was lower than in the wards (P = 0.001) but hospital mortality was comparable between the two groups (P = 0.17). At 6 months follow-up more ICU patients were fully conscious, weaned from ventilation, and decannulated. More patients in the ICU group were at home and were independent or had mildly impaired activities of daily living. More patients in the ward group were residing in long-term care facilities with functional limitations. CONCLUSIONS: MICU patients who undergo tracheostomy may have a good long-term functional and cognitive outcome. More studies are needed to further assess long-term outcomes in these patients.

Intensive Care Admissions and Associated Severity of Influenza B Versus A During Influenza B Vaccine-mismatched Seasons.

Patients admitted to hospital with influenza B and A in Jerusalem, Israel, during the 2015-2016 and 2017-2018 influenza seasons demonstrated similar rates of intensive care unit (ICU) admission and associated disease severity. Most (63%) influenza B ICU patients received influenza B-mismatched trivalent vaccine. These findings call into question the equivalence of trivalent and quadrivalent vaccines in preventing severe influenza B.

Critical care beyond organ support: the importance of geriatric rehabilitation.

Very old critically ill patients pose a growing challenge for intensive care. Critical illness and the burden of treatment in the intensive care unit (ICU) can lead to a long-lasting decline of functional and cognitive abilities, especially in very old patients. Multi-complexity and increased vulnerability to stress in these patients may lead to new and worsening disabilities, requiring careful assessment, prevention and rehabilitation. The potential for rehabilitation, which is crucial for optimal functional outcomes, requires a systematic, multi-disciplinary approach and careful long-term planning during and following ICU care. We describe this process and provide recommendations and checklists for comprehensive and timely assessments in the context of transitioning patients from ICU to post-ICU and acute hospital care, and review the barriers to the provision of good functional outcomes.

Prognosticating the outcome of intensive care in older patients-a narrative review.

Prognosis determines major decisions regarding treatment for critically ill patients. Statistical models have been developed to predict the probability of survival and other outcomes of intensive care. Although they were trained on the characteristics of large patient cohorts, they often do not represent very old patients (age ≥ 80 years) appropriately. Moreover, the heterogeneity within this particular group impairs the utility of statistical predictions for informing decision-making in very old individuals. In addition to these methodological problems, the diversity of cultural attitudes, available resources as well as variations of legal and professional norms limit the generalisability of prediction models, especially in patients with complex multi-morbidity and pre-existing functional impairments. Thus, current approaches to prognosticating outcomes in very old patients are imperfect and can generate substantial uncertainty about optimal trajectories of critical care in the individual. This article presents the state of the art and new approaches to predicting outcomes of intensive care for these patients. Special emphasis has been given to the integration of predictions into the decision-making for individual patients. This requires quantification of prognostic uncertainty and a careful alignment of decisions with the preferences of patients, who might prioritise functional outcomes over survival. Since the performance of outcome predictions for the individual patient may improve over time, time-limited trials in intensive care may be an appropriate way to increase the confidence in decisions about life-sustaining treatment.

The trajectory of very old critically ill patients.

The demographic shift, together with financial constraint, justify a re-evaluation of the trajectory of care of very old critically ill patients (VIP), defined as older than 80 years. We must avoid over- as well as under-utilisation of critical care interventions in this patient group and ensure the inclusion of health care professionals, the patient and their caregivers in the decision process. This new integrative approach mobilises expertise at each step of the process beginning prior to intensive care unit (ICU) admission and extending to long-term follow-up. In this review, several international experts have contributed to provide recommendations that can be universally applied. Our aim is to define a minimum core dataset of information to be shared and discussed prior to ICU admission and to facilitate the shared-decision-making process with the patient and their caregivers, throughout the patient journey. Documentation of uncertainty may contribute to a tailored level of care and ultimately to discussions around possible limitations of life sustaining treatments. The goal of ICU care is not only to avoid death, but more importantly to maintain an acceptable quality of life and functional autonomy after hospital discharge. Societal consideration is important to highlight, together with alternatives to ICU admission. We discuss challenges for the future and potential areas of research. In summary, this review provides a state-of-the-art current overview and aims to outline future directions to address the challenges in the treatment of VIP.