Time-limited Trials Research Articles

Characterizing the Use of Time-Limited Trials in Patients With Acute Respiratory Failure: A Prospective, Single-Center Observational Study.

A time-limited trial (TLT) is a collaborative plan among clinicians, patients, and families to use life-sustaining therapy for a defined duration, after which the patient's response informs whether to continue care directed toward recovery or shift the focus toward comfort. TLTs are a promising approach to help navigate uncertainty in critical illness, yet little is known about their current use. To characterize TLT use in patients with acute respiratory failure (ARF). Prospective 12-month observational cohort study at an U.S. academic medical center of adult ICU patients with ARF receiving invasive mechanical ventilation for greater than or equal to 48 hours. Primary exposure was TLT participation, identified by patients' ICU physician. Patient characteristics, care delivery elements, and hospital outcomes were extracted from the electronic medical record. Among 176 eligible patients, 36 (20.5%) participated in a TLT. Among 18 ICU attending physicians, nine (50%) participated in greater than or equal to 1 TLT (frequency 0-39% of patients cared for). Median TLT duration was 3.0 days (interquartile range [IQR], 3.0-4.5 d). TLT patients had a higher mean age (67.4 yr [sd, 12.0 yr] vs. 60.0 yr [sd, 16.0 yr]; p < 0.01), higher Charlson Comorbidity Index (5.1 [sd, 2.2] vs. 3.8 [sd, 2.6]; p < 0.01), and similar Sequential Organ Failure Assessment score (9.6 [sd, 3.3] vs. 9.5 [sd, 3.7]; p = 0.93), compared with non-TLT patients. TLT patients were more likely to die or be discharged to hospice (80.6% vs. 42.1%; p < 0.05) and had shorter ICU length of stay (median, 5.7 d [IQR, 4.0-9.0 d] vs. 10.3 d [IQR, 5.5-14.5 d]; p < 0.01). In this study, approximately one in five patients with ARF participated in a TLT. Our findings suggest TLTs are used primarily in patients near end of life but with substantial physician variation, highlighting a need for evidence to guide optimal use.

Physician-Reported Facilitators and Barriers for Side Effect Management of Heart Failure Medications.

Physician underprescribing and patient nonadherence are major barriers to the benefits of guideline-directed medical therapy. An important contributor to both underprescribing and patient nonadherence is concern about medication-related side effects. Yet, there are few to no data on approaches used by physicians to: (1) elicit medication-related side effects, (2) attribute these side effects to specific medications, and (3) take appropriate action. The authors conducted semistructured interviews with physicians to identify facilitators and barriers to each critical step of heart failure medication management: elicitation of side effects, attribution of side effects to a medication, and action in response to attributed side effects. Interviews were transcribed and coded using directed content analysis. For elicitation of potential side effects, limited patient communication and family discordance in reporting were key barriers, whereas guiding questions, measurement, and open channels of communication were key facilitators. For attribution of side effects, confounding from other medications, limited time for clinical encounters, and nonspecific symptoms were key barriers, whereas time-limited medication discontinuation trials and medication rechallenges were key facilitators. For taking action, challenges with weighing risks and benefits and physician fear about causing harm or interfering with other clinicians were barriers, whereas patient-physician communication and the results of a medication discontinuation trials and medication rechallenge were facilitators. This study generated key facilitators and barriers to 3 key aspects of heart failure medication management related to side effects that should drive future work to improve heart failure medication management.

Patient-reported outcomes and functional assessments of patients with Alkaptonuria in a 3-year Nitisinone treatment trial

Alkaptonuria is a rare disorder of tyrosine catabolism caused by deficiency of homogentisate 1,2-dioxygenase that leads to accumulation of homogentisic acid (HGA). Deposition of HGA-derived polymers in connective tissue causes progressive arthropathy of the spine and large joints, cardiac valvular disease, and genitourinary stones beginning in the fourth decade of life. Nitisinone, a potent inhibitor of the upstream enzyme, 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces HGA production. As such, nitisinone is a proposed treatment for alkaptonuria. A randomized clinical trial of nitisinone in alkaptonuria confirmed the biochemical efficacy and tolerability of nitisinone for patients with alkaptonuria but the selected primary outcome did not demonstrate significant clinical benefit. Given that alkaptonuria is a rare disease with slow progression and variable presentation, identifying outcome parameters that can detect significant change during a time-limited clinical trial is challenging. To gain insight into patient-perceived improvements in quality of life and corresponding changes in physical function associated with nitisinone use, we conducted a post-hoc per protocol analysis of patient-reported outcomes and a functional assessment. Analysis revealed that nitisinone-treated patients showed significant improvements in complementary domains of the 36-Item Short-Form Survey (SF-36) and 6-min walk test (6MWT). Together, these findings suggest that nitisinone improves both quality of life and function of patients with alkaptonuria. The observed trends support nitisinone as a therapy for alkaptonuria.

Palliative Care for Adult Patients Undergoing Hemodialysis in Asia: Challenges and Opportunities.

This article underscores the importance of integrating comprehensive palliative care for noncancer patients who are undergoing hemodialysis, with an emphasis on the aging populations in Asian nations such as Taiwan, Japan, the Republic of Korea, and China. As the global demographic landscape shifts towards an aging society and healthcare continues to advance, a marked increase has been observed in patients undergoing hemodialysis who require palliative care. This necessitates an immediate paradigm shift to incorporate this care, addressing the intricate physical, psychosocial, and spiritual challenges faced by these individuals and their families. Numerous challenges impede the provision of effective palliative care, including difficulties in prognosis, delayed referrals, cultural misconceptions, lack of clinician confidence, and insufficient collaboration among healthcare professionals. The article proposes potential solutions, such as targeted training for clinicians, the use of telemedicine to facilitate shared decision-making, and the introduction of time-limited trials for dialysis to overcome these obstacles. The integration of palliative care into routine renal treatment and the promotion of transparent communication among healthcare professionals represent key strategies to enhance the quality of life and end-of-life care for people on hemodialysis. By embracing innovative strategies and fostering collaboration, healthcare providers can deliver more patient-centered, holistic care that meets the complex needs of seriously ill patients within an aging population undergoing hemodialysis.

Time-limited trials (TLT) in the intensive care unit : Recommendations from the ethics section of the DIVI and the ethics section of the DGIIN

The rise in intensive care treatment procedures is accompanied by an increase in the complexity of decisions regarding the selection, administration and duration of treatment measures. Whether atreatment goal is desirable in an individual case and the treatment plan required to achieve it is acceptable for the patient depends on the patient's preferences, values and life plans. There is often uncertainty as to whether apatient-centered treatment goal can be achieved. The use of atime-limited treatment trial (TLT) as abinding agreement between the intensive care unit (ICU) team and the patient or their legal representative on atreatment concept over adefined period of time in the ICU can be helpful to reduce uncertainties and to ensure the continuation of intensive care measures in the patients' best interest.

Navigating the uncertainty of critical illness: the role of a time-limited trial.

Navigating the uncertainty of critical illness: the role of a time-limited trial.

The Essential Parallels Between Clinical Practice and the Scientific Method.

This column presents a way of conceptualizing the clinical practice of medicine including psychiatry within the framework of the scientific method. The goal is to aid practicing clinicians as well as trainees. This conceptual framework will improve the care of patients as it applies a discipline relative to giving time-limited trials of the various treatments available and then an assessment of whether the treatment worked adequately or not and what to do in the latter case. In this way, this approach should decrease the risk of excessive multiple medication use to treat a specific patient. Incorporating this conceptual framework early in the training of mental health care prescribers would be desirable.

We Have All the Time in the World: The Law and Ethics of Time-Limited Interventions in Clinical Care.

The authors consider the legal and ethical considerations of offering a time-limited trial of a potentially non-beneficial intervention in the setting of patient or surrogate requests to pursue aggressive treatment. The likelihood of an intervention's success is rarely a zero-sum game, and an intervention's risk-to-benefit ratio may be indiscernible without further information (often, a matter of time).

Defining the Time-limited Trial for Patients with Critical Illness: An Official American Thoracic Society Workshop Report.

In critical care, the specific, structured approach to patient care known as a "time-limited trial" has been promoted in the literature to help patients, surrogate decision makers, and clinicians navigate consequential decisions about life-sustaining therapy in the face of uncertainty. Despite promotion of the time-limited trial approach, a lack of consensus about its definition and essential elements prevents optimal clinical use and rigorous evaluation of its impact. The objectives of this American Thoracic Society Workshop Committee were to establish a consensus definition of a time-limited trial in critical care, identify the essential elements for conducting a time-limited trial, and prioritize directions for future work. We achieved these objectives through a structured search of the literature, a modified Delphi process with 100 interdisciplinary and interprofessional stakeholders, and iterative committee discussions. We conclude that a time-limited trial for patients with critical illness is a collaborative plan among clinicians and a patient and/or their surrogate decision makers to use life-sustaining therapy for a defined duration, after which the patient's response to therapy informs the decision to continue care directed toward recovery, transition to care focused exclusively on comfort, or extend the trial's duration. The plan's 16 essential elements follow four sequential phases: consider, plan, support, and reassess. We acknowledge considerable gaps in evidence about the impact of time-limited trials and highlight a concern that if inadequately implemented, time-limited trials may perpetuate unintended harm. Future work is needed to better implement this defined, specific approach to care in practice through a person-centered equity lens and to evaluate its impact on patients, surrogates, and clinicians.

Frailty and long-term survival among patients in Australian intensive care units with metastatic cancer (FRAIL-CANCER study): a retrospective registry-based cohort study

Recent advances in cancer therapeutics have improved outcomes, resulting in increasing candidacy of patients with metastatic cancer being admitted to intensive care units (ICUs). A large proportion of patients also have frailty, predisposing them to poor outcomes, yet the literature reporting on this is scarce. We aimed to assess the impact of frailty on survival in patients with metastatic cancer admitted to the ICU. In this retrospective registry-based cohort study, we used data from the Australia and New Zealand Intensive Care Society Adult Patient (age ≥16 years) database to identify patients with advanced (solid and haematological cancer) and a documented Clinical Frailty scale (CFS) admitted to 166 Australian ICUs. Patients without metastatic cancer were excluded. We analysed the effect of frailty (CFS 5-8) on long-term survival, and how this effect changed in specific subgroups (cancer subtypes, age [<65 years or ≥65 years], and those who survived hospitalisation). Because estimates tend to cluster within centres and vary between them, we used Cox proportional hazards regression models with robust sandwich variance estimators to assess the effect of frailty on survival time up to 4 years after ICU admission between groups. Between Jan 1, 2018, and March 31, 2022, 30 026 patients were eligible, and after exclusions 21 174 patients were included in the analysis; of these, 6806 (32·1%) had frailty, and 11 662 (55·1%) were male, 9489 (44·8%) were female, and 23 (0·1%) were intersex or self-reported indeterminate sex. The overall survival was lower for patients with frailty at 4 years compared with patients without frailty (29·5% vs 10·9%; p<0·0001). Frailty was associated with shorter 4-year survival times (adjusted hazard ratio 1·52 [95% CI 1·43-1·60]), and this effect was seen across all cancer subtypes. Frailty was associated with shorter survival times in patients younger than 65 years (1·66 [1·51-1·83]) and aged 65 years or older (1·40 [1·38-1·56]), but its effects were larger in patients younger than 65 years (pinteraction<0·0001). Frailty was also associated with shorter survival times in patients who survived hospitalisation (1·49 [1·40-1·59]). In patients with metastatic cancer admitted to the ICU, frailty was associated with poorer long-term survival. Patients with frailty might benefit from a goal-concordant time-limited trial in the ICU and will need suitable post-intensive care supportive management. None.

Emergency Palliative Care: Nongoal Concordant Care and Time-Limited Trials in the Emergency Department.

When advance care plans are not communicated or goals are in conflict, significant family and clinician distress may result. The distress is especially high when potentially nongoal concordant care is expected by surrogates in the emergency department (ED). To demonstrate the effect of off-hour, phone consultations by palliative care clinicians in reducing the family and clinician distress when nongoal concordant care is expected in the ED. A partnership between palliative care and emergency medicine can decrease the burden of decision making and provide opportunities for modeling a goals-of-care discussion by experts in this important procedure.

Video Intervention and Goals-of-Care Documentation in Hospitalized Older Adults

Despite the benefits of goals-of-care (GOC) communication, many hospitalized individuals never communicate their goals or preferences to clinicians. To assess whether a GOC video intervention delivered by palliative care educators (PCEs) increased the rate of GOC documentation. This pragmatic, stepped-wedge cluster randomized clinical trial included patients aged 65 years or older admitted to 1 of 14 units at 2 urban hospitals in New York and Boston from July 1, 2021, to October 31, 2022. The intervention involved PCEs (social workers and nurses trained in GOC communication) facilitating GOC conversations with patients and/or their decision-makers using a library of brief, certified video decision aids available in 29 languages. Patients in the control period received usual care. The primary outcome was GOC documentation, which included any documentation of a goals conversation, limitation of life-sustaining treatment, palliative care, hospice, or time-limited trials and was obtained by natural language processing. A total of 10 802 patients (mean [SD] age, 78 [8] years; 51.6% male) were admitted to 1 of 14 hospital units. Goals-of-care documentation during the intervention phase occurred among 3744 of 6023 patients (62.2%) compared with 2396 of 4779 patients (50.1%) in the usual care phase (P < .001). Proportions of documented GOC discussions for Black or African American individuals (865 of 1376 [62.9%] vs 596 of 1125 [53.0%]), Hispanic or Latino individuals (311 of 548 [56.8%] vs 218 of 451 [48.3%]), non-English speakers (586 of 1059 [55.3%] vs 405 of 863 [46.9%]), and people living with Alzheimer disease and related dementias (520 of 681 [76.4%] vs 355 of 570 [62.3%]) were greater during the intervention phase compared with the usual care phase. In this stepped-wedge cluster randomized clinical trial of older adults, a GOC video intervention delivered by PCEs resulted in higher rates of GOC documentation compared with usual care, including among Black or African American individuals, Hispanic or Latino individuals, non-English speakers, and people living with Alzheimer disease and related dementias. The findings suggest that this form of patient-centered care delivery may be a beneficial decision support tool. ClinicalTrials.gov Identifier: NCT04857060.

Overcoming refusal of treatment in pediatric cancer without legal involvement: A descriptive case series from interviews with pediatric oncologists.

To describe strategies that pediatric oncologists utilize to persuade families to initiate or continue chemotherapy after refusing treatment, we examined transcripts from interviews of oncologists with relevant experience. We identified three cases in which the pediatric oncologists' approaches led to voluntary acceptance of recommended treatment without legal intervention. Strategies used include direct communication with alternative medicine providers, time-limited trial of alternative therapy, and praying with the family. While we cannot conclude whether these approaches could be generalized to other cases, they offer ideas for pediatric oncologists to consider when facing the decision to seek judicial involvement or discontinue persuasive efforts.

The Effects of Agave Fructans in a Functional Food Consumed by Patients with Irritable Bowel Syndrome with Constipation: A Randomized, Double-Blind, Placebo-Controlled Trial.

Irritable bowel syndrome displays three different subtypes: constipation (IBS-C), diarrhea (IBS-D), and mixed (IBS-M). Treatment with dietary fiber is used, with consideration given both to the chemical composition of the fiber and to the different subtypes of IBS. The IBS-D subtype is usually treated with a low-FODMAPs diet, whereas the IBS-C subtype suggests prebiotics and probiotics to promote microbiota restoration. The aim of this study was to assess the effects of employing agave fructans as the soluble fiber of a jelly (Gelyfun®gastro) containing 8 g per serving in the IBS-C group (n = 50), using a randomized, double-blind, time-limited trial for four weeks. We evaluated changes in the frequency and types of bowel movements through the Bristol scale, and the improvement of the condition was evaluated using quality of life (IBS-QOL) and anxiety-depression (HADS) scales. The main results were that the number of bowel movements increased by more than 80%, with at least one stool per day from fifteen days onwards, without a laxative effect for the group treated. Finally, the quality of life with the prebiotic jelly was significantly improved compared to the placebo in all specific domains, in addition to significantly reducing anxiety and depression.

Do They Have a Choice? Surrogate Decision-Making After Severe Acute Brain Injury.

In the early phase of severe acute brain injury (SABI), surrogate decision-makers must make treatment decisions in the face of prognostic uncertainty. Evidence-based strategies to communicate uncertainty and support decision-making are lacking. Our objective was to better understand surrogate experiences and needs during the period of active decision-making in SABI, to inform interventions to support SABI patients and families and improve clinician-surrogate communication. We interviewed surrogate decision-makers during patients' acute hospitalization for SABI, as part of a larger ( n = 222) prospective longitudinal cohort study of patients with SABI and their family members. Constructivist grounded theory informed data collection and analysis. One U.S. academic medical center. We iteratively collected and analyzed semistructured interviews with 22 surrogates for 19 patients. None. Through several rounds of coding, interview notes, reflexive memos, and group discussion, we developed a thematic model describing the relationship between surrogate perspectives on decision-making and surrogate experiences of prognostic uncertainty. Patients ranged from 20 to 79 years of age (mean = 55 years) and had primary diagnoses of stroke ( n = 13; 68%), traumatic brain injury ( n = 5; 26%), and anoxic brain injury after cardiac arrest ( n = 1; 5%). Patients were predominantly male ( n = 12; 63%), whereas surrogates were predominantly female ( n = 13; 68%). Two distinct perspectives on decision-making emerged: one group of surrogates felt a clear sense of agency around decision-making, whereas the other group reported a more passive role in decision-making, such that they did not even perceive there being a decision to make. Surrogates in both groups identified prognostic uncertainty as the central challenge in SABI, but they managed it differently. Only surrogates who felt they were actively deciding described time-limited trials as helpful. In this qualitative study, not all surrogate "decision-makers" viewed themselves as making decisions. Nearly all struggled with prognostic uncertainty. Our findings underline the need for longitudinal prognostic communication strategies in SABI targeted at surrogates' current perspectives on decision-making.

Time-Limited Trials of Intensive Care Unit Care

This Teachable Moment discusses time-limited trials, “an agreement between clinicians and a patient/family to use certain medical therapies over a defined period to see if the patient improves or deteriorates according to agreed-on clinical outcomes.”

P400 Identifying Nutritional targets in Crohn’s disease: INTICO1: a time-limited trial of exclusive enteral nutrition during adult CD remission

Abstract Background During clinical remission in adult Crohn’s disease (CD), impaired health reacted quality of life and fatigue is common, and the nutritional state may be affected by factors such as restrictive eating and altered anatomy from previous inflammation or surgeries. Adults with CD in clinical remission do not routinely undergo nutritional assessments or intervention. The INTICO1 study used a time-limited trial of exclusive enteral nutrition (EEN) to expose and explore nutritionally sensitive aspects of in adults with CD during remission. The extent to which the nutritional state relates to the quality of CD remission and the potential role for nutritional therapies is neither well described nor understood. Methods This was a single arm longitudinal observation study with a dietary intervention. 24 adults in CD remission (Harvey Bradshaw &amp;lt;5, faecal calprotectin &amp;lt;250) underwent assessment of nutritional state at 3 time points; after habitual diet (assessment 1), after 7 days of polymeric EEN (assessment 2) and after a 2-week gradual return to habitual diet (assessment3). Assessments comprised food diary analysis, anthropometry, bio-electrical impedance analysis, routine pathology measures of micronutrient concentration, and patient reported outcome measures (PROMs). Results Assessment 1 (habitual diet) identified individuals with multiple inadequacies of intake (7% (26/368)) micronutrients bloods below the normal laboratory range (see table for analytes) reduced lean mass, low phase angle (PhA) and excessive fatigue (reduced SF-36 vitality). At assessment 2 (post EEN), subjects had fewer deficiencies 4% (16/368), with significant increases seen in Vitamins A, D, E, B2, B6, B9 and the minerals Ca, Cu, Po4 and Se. At visit 3 (return to free diet), micronutrient concentrations reverted toward assessment 1 level, although B6 and B9 remained significantly higher (pairwise comparison visit 1 vs visit 3). BIA measures of nutritional status (PhA) and the SF36 physical function score improved 1 and 2 (5.2 vs 5.4 p&amp;lt;0.01 and 95 v100 p&amp;lt;0.05) and returned to baseline levels on return to free diet (Assessment 3). Conclusion A time-limited trial (7 days) of EEN, given in this setting of adults in CD remission led to changes in micronutrient biochemistry, objective improvement in the bioelectrical properties of the body (increased phase angle) and an improvement in fatigue among the subjects as captured by the SF36-PF. The study suggests that impaired nutritional state and excessive fatigue is likely to be prevalent among adults with CD during remission and may be sensitive to nutritional intervention.

Time-limited trial – searching for rational solutions in the functioning of intensive care units

Time-limited trial – searching for rational solutions in the functioning of intensive care units

The decisional balance, attitudes, and practice behaviors, its predicting factors, and related experiences of advance care planning in Taiwanese patients with advanced cancer

BackgroundPatients with advanced cancer are prone to experience burdensome physical, psychological, and financial consequences. Healthcare providers may not fully appreciate advanced cancer patients’ medical care autonomy, such as at that emboded by Advance Care Planning (ACP), and by doing so may compromise their quality of end-of-life (EOL). Hence, it is essential for healthcare providers to effectively assess and communicate with patients’ regarding their medical decisions before their patients are incapacitated by their disease progression. The purpose of this investigation was to describe the decisional balance, attitudes, and practice behaviors of ACP and its predictors of ACP-related experiences in Taiwanese patients with advanced cancer.MethodsThis cross-sectional, descriptive study employed a mixed-methodsquantitative and qualitative design with a sample of 166 patients that were purposely recruited from in-patient oncology units at a regional teaching hospital in southern Taiwan. Study data consisted of patient replies to a 34-item self-report tool, Decisional Balance, Attitudes, Practice Behaviors of ACP (DAP-ACP) and 4 semi-structured questions.ResultFindings indicated that, in general, study participants exhibited favorable ACP-decisional balance and positive ACP-attitudes & practice behaviors. The results also indicated that gender, educational level, and cancer diagnosis were associated with significant differences on the “ACP-decisional balance” and “ACP-attitudes” scales. In addition, our findings documented that the participants’ gender and educational level were significant predictors of both ACP-decisional balance and ACP-attitudes. Furthermore the participants’ ACP-practice behaviors were predicted by ACP-decisional balance, but not with their ACP-attitudes. The qualitative analysis of the semi-structured questions identified six themes in responses to current medical decision making (e.g., compliance with physician instructions, family engagement in treatment decision-making); and eight themes pertaining to future ACP-related concerns were identified (e.g., family conflict, effectiveness of time-limited trials).ConclusionTo promote patients’ engagement in ACP, the healthcare professional need to assess and advocate patients’ concerns or attitudes regarding ACP in a timely manner. In addition, factors or concerns that might influence patients’ responses to ACP derived from both the quantitative and qualitative findings of this current study need to be considered especially in initiating the dialogue regarding ACP with patients with advanced cancer.Trial registrationNo. CYCH 2,019,072, Date of registration 5 Dec 2019.

Editors' Note: Part 3: Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy.

“Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy” by Geerts et al. compared the administration of IVIG with placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. We summarized (1) an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article) in the October 19, 2021, Editors' Note and (2) an exchange between Wilder-Smith et al. and Faber et al. in the January 18, 2022, Editors' Note.[1][1],[2][2] Oaklander et al. now comment that while the trial used a subjective outcome (pain intensity), an objective assessment (such as autonomic function test scores) could have enhanced the methodology. They also advocate against the extrapolation of these results to all patients with SFN, noting that patients with autoimmune disorders who may benefit from IVIG may not be readily apparent, so it is beneficial to create guidelines triaging patients with SFN who may benefit from a time-limited trial of IVIG. Finally, they express concern that payors may deny treatment to some patients who could benefit, particularly those who are immune-mediated. Faber et al. respond that changes in the Pain Intensity Numerical Rating Scale score are clinically relevant and the sensitivity of autonomic function testing results in isolation to detect autonomic dysfunction in SFN is low in clinical practice. They agree that patients with immune-mediated SFN may benefit from IVIG and emphasize that their study was not intended to focus on that patient population. However, they suggest that randomized studies with valid and reliable outcome measures are needed to evaluate the role of IVIG in patients with SFN that could potentially be immune-mediated. “Intravenous Immunoglobulin Therapy in Patients With Painful Idiopathic Small Fiber Neuropathy” by Geerts et al. compared the administration of IVIG with placebo for patients with idiopathic small fiber neuropathy (SFN) and found no significant difference in the Pain Intensity Numerical Rating Scale score. We summarized (1) an exchange about these findings between Wilder-Smith and Spoendlin and Faber (a coauthor on the article) in the October 19, 2021, Editors' Note and (2) an exchange between Wilder-Smith et al. and Faber et al. in the January 18, 2022, Editors' Note.1,2 Oaklander et al. now comment that while the trial used a subjective outcome (pain intensity), an objective assessment (such as autonomic function test scores) could have enhanced the methodology. They also advocate against the extrapolation of these results to all patients with SFN, noting that patients with autoimmune disorders who may benefit from IVIG may not be readily apparent, so it is beneficial to create guidelines triaging patients with SFN who may benefit from a time-limited trial of IVIG. Finally, they express concern that payors may deny treatment to some patients who could benefit, particularly those who are immune-mediated. Faber et al. respond that changes in the Pain Intensity Numerical Rating Scale score are clinically relevant and the sensitivity of autonomic function testing results in isolation to detect autonomic dysfunction in SFN is low in clinical practice. They agree that patients with immune-mediated SFN may benefit from IVIG and emphasize that their study was not intended to focus on that patient population. However, they suggest that randomized studies with valid and reliable outcome measures are needed to evaluate the role of IVIG in patients with SFN that could potentially be immune-mediated. [1]: #ref-1 [2]: #ref-2