This comprehensive review of 25 studies explores variables to identify and define subtypes of complex regional pain syndrome, aiding the development of targeted treatments. To systematically identify and summarize possible subtypes of complex regional pain syndrome (CRPS), we searched MEDLINE, Embase, Cochrane, Scopus, and Web of Science for original studies reporting or investigating at least one subtype within a group of patients with CRPS. The search retrieved 4239 potentially relevant references. Twenty-five studies met our inclusion criteria and were included in the analysis. Complex regional pain syndrome phenotypes were investigated based on the following variables: clinical presentation/sensory disturbances, dystonia, skin temperature, disease duration, onset type, CRPS outcome, and neuropsychological test performance. Support was found for the following CRPS subtypes: CRPS type I, CRPS type II, acute CRPS, chronic CRPS, centralized CRPS, cold CRPS, warm CRPS, inflammatory CRPS, dystonic CRPS, nondystonic CRPS, familial CRPS, and nonfamilial CRPS. It is unclear whether these are distinct or overlapping subtypes. The results of this comprehensive review can facilitate the formulation of well-defined CRPS subtypes based on presumed underlying mechanisms. Our findings provide a foundation for establishing and defining clinically meaningful CRPS subtypes, with the ultimate goal of developing targeted and enhanced treatments for CRPS. For example, the original 1994 diagnostic nomenclature specified 2 subtypes reflecting the previous distinction between older diagnoses of reflex sympathetic dystrophy and causalgia: CRPS type I  and CRPS type II , respectively.40 However, despite increasing research in the field of CRPS, current treatment regimens remain inadequate, and it is unclear whether the CRPS type I vs CRPS type II subtype distinction meaningfully affects treatment outcomes.8From its inception as a diagnostic term in 1994, CRPS was intended to serve as an umbrella diagnosis that encompassed a variety of painful disorders.6 To develop more effective CRPS treatments, it is critical to identify relevant CRPS subtypes  that specific treatments with known mechanisms of action can target . Several subtypes have been proposed in the literature, but no systematic summary of the evidence is available. Hence, the aim of this review was to systematically identify and summarize the evidence for subtypes in CRPS.It is possible that to date, the lack of significant efficacy in large pharmaceutical trials may arise because of the existence of multiple CRPS subtypes in trial samples selected based on current broad diagnostic criteria  that dilute beneficial treatment effects for a responsive patient subtype when grouped together. Different disease mechanisms may underlie different CRPS clinical phenotypes  and therefore may require different types of treatments.45 and the study was registered in the Open Science Framework (https://osf.io).This systematic review was conducted in accordance with the recommendations by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA statement),We performed a comprehensive electronic search in MEDLINE (OvidSP), Embase (Elsevier), Cochrane, Scopus, and Web of Science from inception to July 2022 to identify relevant references. The terms for the search strategies were identified through discussion between an information specialist and the review team, by scanning the background literature and by browsing the MEDLINE Thesaurus (MeSH). The combinations of the following search keywords and MeSH terms were used in title, abstract and keywords: “reflex sympathetic dystrophy,” “complex regional pain syndrome,” ‘CRPS,” “algodystrophy,” “Sudeck” AND “subgroup,” “subtype,” “subset,” “phenotype,” “cluster.” The search was performed by a professional information specialist. To ensure the completeness of the literature search, 2 reviewers who were experienced clinicians and researchers in the field of CRPS screened bibliographies of all included studies and retrieved articles in an additional hand search. All potentially eligible references were included in the full-text review (inclusion criteria applied).The eligibility criteria for inclusion in the current systematic review were (1) human studies, (2) established diagnosis of CRPS by applying disease-specific diagnostic criteria, and (3) reporting of at least one subtype  within a CRPS sample. We applied no language restriction. Opinion papers, letters, conference abstracts and review articles were excluded.48 These criteria assess 8 critical aspects of study design for noncomparative clinical studies and an additional 4 aspects of study design for comparative clinical studies. Each item is given a score of zero if information is not reported, one if information is reported but inadequate, and 2 if information is reported and adequate. The sum score results in a maximum score of 16 for noncomparative studies and 24 for comparative studies. Each score was then converted into a percentage to harmonize the scoring system. Depending on the score achieved, studies were qualified as either having low-risk of bias (≥75%), moderate-risk of bias (50% ≤ score <75%), or high-risk of bias (<50%).The quality of all studies was assessed using the MINORS criteria .Citations from the initial search results of each database were exported to EndNote , and duplicates were removed. The titles and abstracts were screened and reviewed by 2 authors (L.K. and F.B.). Then, full texts of potential studies were retrieved and independently reviewed in detail for inclusion based on the predetermined criteria. Discrepancies between the 2 authors were resolved by discussion, and a third author (S.B.) was consulted if consensus could not be reached.One author (F.B.) extracted the data from the included studies into a piloted standardized data collection form, and another author (L.K.) cross-checked the extracted data. The following data were extracted: author, year, study design, diagnostic criteria, number of participants with CRPS and their age, sex, site of CRPS, and disease duration. Subtypes were investigated or identified, and the main findings were also extracted.52 In total, 25 studies were included in the final analysis. Figure The search retrieved 8974 total records. With duplicates removed before screening, there were 4239 potentially relevant references. After screening titles and abstracts, the full text of 94 abstracts was reviewed. Of these, 74 references were excluded because they did not meet the inclusion criteria, leaving 20 included studies. Five additional studies were added based on the hand search.57 Most studies employed a cross-sectional (N = 16)55 or cohort (N = 6)38 design. Some of the studies limited the inclusion to patients with CRPS type I (N = 8),55 and some studies did not report whether patients had CRPS type I or CRPS type II (N = 6).57 The majority of studies included patients with upper and lower extremity CRPS (N = 15).57 A total of 4908 patients  with a mean age of 46.9 years (SD 5.1) were included in the analysis. All studies predominantly included female participants (mean 68.5%) consistent with the sex difference previously noted in CRPS prevalence.46 The mean disease duration across studies ranged from 4 months25 to 9.3 years53 .The characteristics of the studies and the patient samples for each are summarized in Table 54 8 studies with a moderate risk of bias,55 and 1 study with high risk of bias57 . Of the 25 studies included, 16 were classified as having low risk of bias,Phenotyping in the included studies was based on the following variables: clinical presentation/sensory disturbances, dystonia, skin temperature (warm vs cold CRPS), disease duration, onset type , CRPS outcome, and neuropsychological test performance. Two studies investigated subtypes based on biomarkers of inflammation. Table 39 In the first study,8 a cluster analysis based on the presence of signs/symptoms within the 4 CRPS diagnostic sign/symptom domains  led to 3 possible subtypes: (1) a predominately vasomotor subtype, (2) a predominately neuropathic pain/sensory abnormalities subtype, and (3) a subtype described as florid CRPS with the presence of broad CRPS features and the highest levels of motor/tropic signs together with osteopenia on bone scan in the affected limb. Pain duration did not differ between the 3 subtypes. Patients were mainly CRPS type I (67%). However, abnormalities on EMG/nerve conduction velocity testing were most common in the neuropathic/sensory abnormalities subtype, leading the authors to conclude that differences between the vasomotor subtype and the neuropathic/sensory abnormalities subtype may correspond to CRPS type I and CRPS type II, respectively (low risk of bias).Three studies examined clinical or sensory phenotyping variables and found support for CRPS subtypes based on these data, although the identified subtypes were not identical.18 identified 3 primary CRPS subtypes: (1) a peripheral inflammation subtype that experienced edema, skin color changes, skin temperature changes, sweating, and tropic changes in the affected limb, (2) a central subtype reflecting CNS pathophysiology  who also experienced cold hyperalgesia in the affected limb, and (3) a mixed subtype (combination of both subtypes above). The 3 subtypes did not differ in relation to age, CRPS duration, sex, or CRPS type I vs CRPS type II. Fewer patients with a cold limb were in the peripheral subtype (10%) than the mixed subtype (25.9%), and the central subtype had more cases of CRPS following minor injury than the peripheral and mixed groups (low risk of bias).In another low risk of bias cluster analysis, this time based on objective CRPS signs only, Dimova et al.39 identified 3 CRPS subtypes based on the pattern of quantitative sensory testing (QST) results: (1) a subtype with temperature allodynia (to warm or cold), (2) a subtype with elevated warmth and cold detection thresholds , and (3) a subtype with both elevated thermal detection thresholds and temperature allodynia. Paroxysmal pain  and allodynia to touch were more prevalent in patients displaying the thermal allodynia subtype  compared with patients without thermal allodynia. The authors attributed this to hyperexcitable superficial skin nociceptors and spinal central sensitization in these patients. Pain intensity and distribution of CRPS type I and type II did not differ between the 3 subtypes and, thus, pain appeared to be unrelated to small nerve fiber degeneration. The authors did not assess for any relation to disease duration (moderate risk of bias).In a third clinical/sensory phenotyping study, Lunden et al.53 Van Rooijen et al.53 assessed whether patients with and without dystonia  differ genetically on alleles of the human leukocyte antigen system (HLA). Human leukocyte antigen-B62 was associated with CRPS with dystonia, whereas HLA-DQ8 was associated with both subgroups , suggesting that CRPS subtypes with and without dystonia may be genetically different but overlapping disease entities (low risk of bias).Differences between CRPS patients with vs without dystonia have been investigated in 3 studies.51 The CRPS without dystonia subtype showed a loss of function to warmth detection, cold detection, and a gain of function to cold pain and pressure pain in the CRPS limb. The CRPS with dystonia subtype experienced a similar loss and gain of function but in addition experienced a loss of function for vibration detection and two-point discrimination and had a greater gain of function for pressure pain than the CRPS without dystonia subtype. Patients with the CRPS with dystonia subtype were also slower at recognizing the affected limb than those with the CRPS without dystonia and performed more poorly on finger tapping than those with the CRPS without dystonia subtype. Pressure-pain thresholds inversely correlated with performance on finger tapping in all 3 groups and with dystonia severity, suggesting that muscle hyperalgesia in the CRPS limb may contribute to motor impairments (low risk of bias).Another study examined the relation between sensory function assessed using QST and motor performance in CRPS with and without dystonia, as well as in healthy controls.52 Widespread muscle hyperalgesia, in particular to pressure, was found in unaffected body parts. No differences were found between dystonia-related CRPS subtypes except for lower vibration thresholds relative to the unaffected leg of CRPS patients with dystonia (low risk of bias).To see whether sensory dysfunction is widespread throughout the body in CRPS patients and whether it relates to the presence of dystonia, the third study investigated sensory function using QST in unaffected body parts of CRPS patients.55 In some studies, support for warm and cold CRPS subtypes was found.55 Definitions of what constitutes a warm and cold CRPS limb differed slightly between the studies, ranging from a difference of 0.60°C to 1.0°C between the CRPS limb and the contralateral limb .Six studies investigated subtypes based on whether the skin temperature of the CRPS limb could be classified as warm or cold relative to the unaffected limb.54 used QST to explore differences in sensory processing between warm and cold CRPS subtypes 8 years after diagnosis. All patients had CRPS type I. Both the warm and cold subtypes exhibited pressure hyperalgesia in the affected limb and a worsening of this with disease progression. However, 8 years after diagnosis, patients initially diagnosed with the cold CRPS subtype had poorer clinical outcomes and showed persistent signs of central sensitization. Patients with cold CRPS also experienced more pain from electrical stimulation than those with the warm CRPS subtype (moderate risk of bias).Vaneker et al.55 Dirckx et al.19 conducted a retrospective analysis of CRPS patients to assess signs of inflammation in patients with warm, cold, and intermediate temperature subtypes. Proinflammatory cytokine levels  were determined in fluid from artificially induced suction blisters made on the CRPS limb and the contralateral limb. The 3 subtypes did not differ in levels of these proinflammatory cytokines in the CRPS limb vs the contralateral limb. Nonetheless, compared with the warm CRPS subtype, the cold CRPS subtype consisted of younger patients with longer CRPS duration. The authors did not report whether patients were CRPS type I and/or CRPS type II (moderate risk of bias). In another study, a cluster analysis based on signs and symptoms of inflammation in predominantly CRPS type I patients (85%) found evidence for a warm CRPS subtype characterized by a warm, red, edematous, sweaty extremity, and a statistically distinct cold CRPS subtype marked by a cold, blue, and less edematous limb. Pain duration was again longer in patients with the cold CRPS subtype. However, 16% of patients in the cold CRPS group had a pain duration of <6 months. Patients initially displaying the warm CRPS subtype scored higher than the cold CRPS subtype on a clinically derived inflammation score, although inflammation decreased over the 3-month follow-up. This pattern was not observed in cold CRPS.9 The 2 subtypes did not differ regarding pain intensity (low risk of bias).Three studies looked at the relation of skin temperature in the CRPS limb with inflammation.55 assessed whether the effectiveness of bisphosphonates in CRPS type I patients was influenced by several clinical and demographic factors, including warm vs cold subtypes. Responsiveness to bisphosphonates was predicted by displaying the warm CRPS subtype, as well as shorter CRPS duration and fracture as an initiating event (moderate risk of bias).In another study addressing warm vs cold CRPS subtypes, Varenna et al.22 evaluated whether upregulated cutaneous expression of α1-adrenoceptors (α1-AR) is a source of pain in CRPS patients by comparing patients and healthy controls. They also looked at CRPS subtypes based on limb temperature  among other subgroup analyses . α1-AR immunoreactivity was greater in nerve bundles of the reticular dermis (but not in the epidermis and blood vessels) of CRPS patients than healthy controls both in the CRPS limb and the contralateral limb. α1-AR immunoreactivity was also greater in the affected than in the contralateral limb. Greater α1-AR immunoreactivity of nerve bundles may be associated with pain in CRPS because α1-AR immunoreactivity was greater in dermal nerve bundles in the CRPS limb of a possible CRPS subtype that experienced evoked pain and pinprick hyperalgesia to injection of the α1-AR agonist phenylephrine. However, α1-AR immunoreactivity was similar in patients with the cold vs warm subtypes  for all regions of interest  (low risk of bias).Drummond et al.25 Alexander et al.1 evaluated plasma levels of cytokines, chemokines, and their soluble receptors in CRPS patients compared with gender-matched and age-matched healthy controls. Using cluster analysis, 2 distinct clusters were identified in CRPS patients: a subtype with levels similar to healthy controls (noninflammatory subtype) and a subtype with elevated levels of most plasma cytokines and soluble receptors (inflammatory subtype). There was no difference in CRPS duration between the 2 groups. However, in the inflammatory subtype, increased plasma levels of TNF-alpha correlated positively with disease duration. No difference in inflammatory markers between CRPS type I and CRPS type II subtypes was observed. Additional cluster analyses confirmed the positive correlations between TNF-alpha levels and both CRPS duration and severity in those patients with elevated levels of TNF-alpha who did not have an increase in its soluble receptor sTNF-RII. For patients with increased levels of the interleukin IL-1beta (and the interleukin soluble receptor sIL-1RI) without an increase in the interleukin soluble receptor sIL-1RII and the interleukin 1 receptor antagonist IL-1Ra, IL-1beta levels similarly correlated positively with both CRPS duration and severity (low risk of bias).Two studies investigated subtypes based on markers related to inflammation.25 compared matrix metalloproteinases (MMP)-2 and MMP-9 concentrations in skin and serum of patients with CRPS, patients with other pain conditions, and healthy controls and related this to clinical data and QST results. The authors did not report the proportion of CRPS type I vs CRPS type II patients in the sample. These 2 enzymes play an important role in inflammation. Matrix metalloproteinases-2 was increased bilaterally in the skin of CRPS patients and MMP-9 in the ipsilateral CRPS skin relative to non-CRPS controls. Findings suggested that MMP-2 and MMP-9 are differently expressed depending on the clinical phenotype of CRPS; low ipsilateral MMP-2 was associated with trophic changes, and contralateral MMP-2 was associated inversely with CRPS severity. Higher ipsilateral and contralateral MMP-9 was associated with higher CRPS severity (low risk of bias). These patterns of MMP-2 and MMP-9 may support distinct inflammatory subtypes of CRPS.Escolano-Lozano et al.30 As mentioned earlier in the section on skin temperature phenotyping, Drummond et al.22 also evaluated upregulated cutaneous expression of α1-AR in relation to CRPS duration in a study with a low risk of bias. Three rationally derived duration categories were predetermined: (1) acute CRPS, <12 months; (2) intermediate CRPS, 11–36 months; and (3) chronic CRPS, >36 months. α1-AR immunoreactivity was greater in nerve bundles within the CRPS limb of patients with the acute CRPS subtype compared with both the intermediate and chronic CRPS subtypes but was similar across duration subtypes in the contralateral limb. Furthermore, α1-AR immunoreactivity was greater on dermal nerves in the CRPS limb than that in the contralateral limb irrespective of CRPS duration subtype. However, α1-AR immunoreactivity in the epidermis was greater bilaterally in patients with the acute or intermediate CRPS subtypes compared with the chronic subtype for patients with CRPS type II, whereas the opposite was seen in CRPS type I. Furthermore, α1-AR immunoreactivity on blood vessels was greater in the acute CRPS subtype than either the intermediate or chronic CRPS subtype.Five studies explored CRPS subtypes related to disease duration.21 assessed hemisensory disturbances in relation to the same CRPS duration subtypes above . In both, CRPS type I and CRPS type II, the distribution and intensity of mechanical hyperalgesia was similar in patients with acute, intermediate, and chronic CRPS, but patients with the chronic CRPS subtype experienced increased cold pain ratings and increased sharpness ratings to repeated pinprick in the ipsilateral forehead compared with the contralateral forehead. This was not seen in the acute or intermediate CRPS subtypes. Patients with chronic CRPS subtype was also more sensitive to thermal stimuli on both sides of their body than those with the acute or intermediate CRPS subtypes and was more likely to experience pain in an additional limb. These findings together suggest that heightened excitability of nociceptive pathways spreads centrally with increasing CRPS duration, for instance, to sensory convergence points in the brain stem or higher brain centers (low risk of bias).Another study by Drummond et al.11 studied CRPS duration subtypes based on slightly different disease durations than Drummond et al.22  and looked at the presenting signs and symptoms for each subtype in patients with CRPS type I. Sensory signs  and motor signs (except limited range of motion) occurred more frequently in patients with a longer disease duration subtype (>6 months) than those with a short disease duration subtype (<2 months), with similar differences regarding changes in nail growth (but not skin or hair growth). Vasomotor and sudomotor signs were less frequent in patients with longer disease duration (>6 months) (low risk of bias).De Boer et al.4 separated CRPS patients (type I and II) into 2 duration subtypes based on a 3-month CRPS duration cutoff  when looking at keratinocyte and mast cell proliferation in CRPS skin biopsies and identifying the cellular source of upregulated TNF-alpha, IL-6, and tryptase. Epidermal thickness and keratinocyte expression was increased in CRPS affected skin compared with the contralateral skin of patients with acute CRPS and decreased in affected skin of patients with chronic CRPS. Increases in TNF-alpha and IL-6 were more frequent in affected skin from acute CRPS patients than in those with chronic CRPS. Furthermore, tryptase-positive dermal mast cell numbers were increased in affected skin of acute CRPS patients but similar to the contralateral limb in patients with chronic CRPS. Temperature asymmetry (warm CRPS limb) correlated positively with the number of tryptase-labelled mast cells (low risk of bias).Birklein et al.30 defined CRPS duration subtypes based on the sequential stages proposed by Bonica5 with a time since inciting injury of 12 months or below defined as an acute CRPS subtype and a time since injury above 12 months as a chronic CRPS subtype. Thermal QST was investigated in the CRPS limb and the contralateral limb compared with a group of age-matched and gender-matched healthy controls. Patients with the acute CRPS subtype experienced warm and cold hyperalgesia, as well as warm and cold hypoesthesia, in the CRPS limb relative to the contralateral limb. Thermal hyperalgesia was not as severe as in the chronic CRPS subtype, and warm and cold hypoesthesia were more severe in the chronic CRPS subtype compared with acute CRPS. Only patients with the acute CRPS subtype experienced paradoxical heat sensations. All QST changes were also somewhat present in the contralateral limb relative to healthy controls. The difference in skin temperature between the acute and chronic CRPS subtypes was significant with a warmer CRPS limb in the acute subtype and a colder CRPS limb in the chronic subtype compared with the contralateral limb (low risk of bias).Huge et al.26Five studies considered whether the type of initiating event or injury including major peripheral nerve lesion (CRPS type I vs CRPS type II) are relevant for subtyping patients.22 who investigated the involvement of α1-AR in CRPS, subtyping by CRPS type I vs CRPS type II was also assessed. On average, α1-AR immunoreactivity in CRPS-affected skin was greater in nerve bundles of patients with CRPS type II than in those of patients with CRPS type I, particularly within the distribution of the injured nerve. However, no difference was seen for the contralateral limb. Furthermore, α1-AR immunoreactivity was greater on dermal nerves in the CRPS limb than the contralateral limb irrespective of CRPS type I or CRPS type II. Both patients with CRPS type I and CRPS type II were among the subgroup of patients who experienced increased pain and hyperalgesia to phenylephrine injection. As mentioned above, a difference in α1-AR immunoreactivity over time was noted across the CRPS type I and CRPS type II subtypes, with α1-AR immunoreactivity in the epidermis being greater bilaterally in CRPS type II patients with the acute or intermediate subtype compared with patients with chronic CRPS type II, whereas the opposite pattern over time was seen in CRPS type I. α1-AR immunoreactivity on blood vessels was greater in both limbs of patients with CRPS type II compared with patients with CRPS type I (low risk of bias).In the previously mentioned study by Drummond et al.21 also included CRPS type I and CRPS type II as formal subtypes. Patients with the CRPS type I subtype were more often female and more often had pain in more than one limb than those with the CRPS type II subtype. Sensory deficits and allodynia were more common in the CRPS-affected limb in patients with CRPS type II than in those with CRPS type I, but CRPS type I patients with the chronic CRPS subtype more often had pressure-pain sensitivity and allodynia in the uninjured limb on the symptomatic side of the body than in patients with chronic CRPS type II. Hyperalgesia to repeated pinprick was greater in the forehead ipsilateral to the CRPS limb than contralaterally in both chronic CRPS type I and chronic CRPS type II but not in intermediate and acute CRPS. Thermal thresholds and thermal ratings were similar in CRPS type I and CRPS type II (low risk of bias).In the study on hemisensory disturbances described previously, Drummond et al.26 also investigated differences in somatosensory signs between CRPS type I and CRPS type II subtypes using a full QST battery in the affected limb. Patients with CRPS type I and type II had almost identical sensory profiles in terms of hyperalgesia, allodynia, and thermal detection thresholds, although a loss of mechanical detection occurred more frequently in patients with the CRPS type II subtype. Correlations between QST findings and symptom duration were only modest. Hyperalgesia/allodynia without loss of detection (only gain) was more common in the CRPS type I subtype than in the CRPS type II (low risk of bias).Gierthmühlen et al.14 studied a possible familial CRPS subtype by evaluating families with a history of CRPS and comparing clinical characteristics of these patients with those of nonfamilial CRPS. Overall, patients with the familial CRPS subtype had younger age at onset, CRPS that more often affected multiple extremities, and more frequent dystonia. The study did not report whether patients had CRPS type I or CRPS type II (moderate risk of bias).De Rooij et al.15 a cross-sectional exploration to compare phenotypic characteristics of patients with spontaneous CRPS vs trauma-induced CRPS was performed. Findings suggested that patients with the spontaneous CRPS subtype were younger at CRPS onset and had a longer disease duration. Clinical presentation and sex distribution were similar in both subtypes. Again, the authors did not address whether patients had CRPS type I or CRPS type II (moderate risk of bias).In another study by de Rooji et al.,57 de Mos et al.13 employed cluster analysis to derive 3 subtypes based on CRPS outcome  as reflected in the number of signs and symptoms that were present 2 years or more after the onset in a group of mainly CRPS type I patients (97%). Patients with the poor outcome subtype more often had upper extremity CRPS and a cold CRPS phenotype and less often reported fractures as the initiating event. Patients with the poor outcome subtype also reported ongoing disease progression and adjustments in employment . All patients with the poor outcome subtype still fulfilled the IASP CRPS criteria at the time of follow-up assessment. No difference in CRPS duration was observed between the outcome groups (low risk of bias).In 3 studies, possible CRPS subtypes were based on the long-term clinical outcomes of CRPS.20 used a cross-sectional design to determine whether clinical characteristics differed between 2 CRPS subtypes: (1) patients who experience a pain increase in the CRPS limb to forehead cooling and (2) patients who do not experience a pain increase to forehead cooling. Patients who experienced a pain increase to forehead cooling also experienced greater pain in the CRPS limb before forehead cooling and were in general more sensitive to stimuli on the forehead, in particular on the side ipsilateral to the CRPS limb, and were more sensitive to pressure pain in the limbs. Together, this led the authors to conclude that the pain increase group was experiencing a disturbance in central somatosensory processing and pain modulation. Pain duration was greater in patients with this central somatosensory disturbance subtype. The subtypes did not differ in terms of proportion of CRPS type I vs CRPS type II (moderate risk of bias).Drummond and Finch57 identified acute, chronic (3–6 months after onset), and refractory CRPS subtypes. Specifically, findings highlighted the importance of recognizing the chronic refractory subtype because of its extremely severe disabling course and resistance to treatment. The authors noted that their refractory subtype group consisted exclusively of women aged 18 to 40 years, and neurological symptoms were always present . However, this study had a high risk of bias.Finally, through an observational review of an institutional CRPS registry, Zyluk and Puchalski38 conducted a battery of tests that assess executive function, naming/lexical retrieval, and declarative memory in CRPS patients. Based on a two-step cluster analysis, the following 3 subtypes were identified: (1) a cognitively normal subtype with scores in the average range on all tests, (2) a dysexecutive subtype with mild impairment or low average performance on working memory/verbal fluency tests, and (3) a global cognitive dysfunction subtype with scores in the low average/borderline range on all tests but with particularly low scores on naming/declarative memory tasks. The latter 2 groups were equally impaired on executive function tests. The global dysfunction CRPS subtype presented with fewer years of education compared with the other groups and with a higher score on the Beck Depression Inventory-II than the cognitively normal subtype. However, these differences in education and depression levels did not statistically account for the differences in neuropsychological variables. Overall, the 3 cognitive subtypes did not differ in terms of pain levels, CRPS duration, medication use, or the number of CRPS-affected limbs. The authors did not report on the distribution of CRPS type I and CRPS type II (moderate risk of bias).One study investigated and found support for neuropsychological subtypes in CRPS. Libon et al.This review systematically identified and summarized studies investigating possible subtypes of CRPS. The findings from the included studies provide support for the following subtypes: CRPS type I, CRPS type II, acute CRPS, chronic CRPS, centralized CRPS, cold CRPS, warm CRPS, inflammatory CRPS, dystonic CRPS, nondystonic CRPS, familial CRPS, and nonfamilial CRPS. It is unclear whether these are distinct or overlapping subtypes. There was also limited evidence that there may be CRPS subtypes with distinctive impairments in cognitive function.22 A difference in clinical presentation with vasomotor signs and symptoms being more common in CRPS type I, and neuropathic/sensory abnormalities more common in CRPS type II8 also point to possible differences in some of the mechanistic underpinnings. Consistent with this, sensory loss to mechanical stimuli was more frequent in patients with CRPS-type II than CRPS-type I.26 However, there was disagreement as to whether allodynia is more frequent in CRPS type II than in CRPS type I26 or of similar frequency.26 It is possible that the greater sensory loss in CRPS type II arises as a result of the peripheral nerve lesion leading to the type II diagnosis.26 However, peripheral nerve damage, albeit of small nerve fibers, has also been suggested to occur in CRPS type I.44 Nonetheless, damage to small fibers would be expected to lead to sensory loss to thermal QST tests  rather than mechanical stimuli (large fibers), which did not differ between CRPS type I and type II.26 The relevance of the CRPS type I and CRPS type II subtype nomenclature has been debated ever since the terms replaced the former diagnoses of reflex sympathetic dystrophy (CRPS type I) and causalgia (CRPS type II). During the development of the Budapest criteria, there were considerations to remove this division because there was broad agreement that the clinical presentation and therapeutic response was not significantly different.29 Primarily for historical reasons, the terms were retained.29 Findings in this review provide a rationale for further research into differences between CRPS type I and CRPS type II. Such studies need to carefully differentiate patients with CRPS type II from those with posttraumatic neuralgia, which may display similar sensory–motor changes albeit confined to the lesioned nerve territory. For patients with CRPS type II, sensory changes must go beyond the territory of the lesioned nerve.Surprisingly, only a few of the studies aimed to formally assess differences between CRPS type I and CRPS type II patients, although many of the studies have mentioned the contribution of CRPS type I and CRPS type II to their findings. Absence of formal comparisons may in part be due to the much smaller samples of CRPS type II patients in most studies. Some studies did not report or distinguish between whether patients had CRPS type I or CRPS type II. There were indications from the studies that CRPS type I and CRPS type II may be relevant subtypes. For instance, different mechanisms may contribute to the upregulation of adrenoceptors in CRPS type I and CRPS type II patients as α1-AR immunoreactivity in the skin was differentially expressed in CRPS type I and CRPS type II patients and was associated with CRPS duration in different directions in the 2 groups.26 Some work suggest that this centralization with chronicity may be more common in CRPS-type I because patients with chronic CRPS type I had a greater spread of pain and hyperalgesia outside the CRPS limb ipsilaterally compared with chronic CRPS type II.21 Also consistent with the occurrence of central changes with chronicity, de Boer et al.11 found allodynia, hyperalgesia, and motor signs to be more frequent in the CRPS limb of patients with a longer CRPS duration. The finding of a central disturbance in somatosensory processing (perhaps a switch from inhibition of nociception to facilitation) in a subgroup of patients with a longer pain duration irrespective of CRPS type I or II provide further support for central changes in persistent CRPS.20 The presence of pain and increased sensitivity outside the CRPS-affected limb in chronic/persistent CRPS, as noted above,26 may reflect the nociplastic process of central sensitization.56 At which time point during the disease course these central aspects come into play is unclear and needs to be investigated further. In the included studies, disease durations that defined chronic CRPS differed widely from >3 months to 66 months, and some of the studies referred to pain duration rather than CRPS duration.Regardless of CRPS-type I vs CRPS-type II subtype status, sensitivity outside the CRPS limb seemed to intensify in patients with chronic/persistent CRPS, which points to changes in the nociceptive system centrally with increasing disease duration irrespective of CRPS type I or II.47 but some have found that these processes remain intact . In some studies, these disturbances correlated positively with pain duration,34 and, in other studies, they did not.47 Thus, there is a need for more studies into possible alterations in central pain inhibitory systems. In defining subtypes, it may be more valuable to focus on a subtype reflecting presumed centralized mechanisms based on clinical features rather than a subtype defined by an arbitrary pain duration cutoff because a centralized pathophysiology may exist in a subgroup of CRPS patients irrespective of chronicity. In the study by Dimova et al.,18 a statistically distinct centralized pathophysiology subtype appeared to be unrelated to CRPS duration. The presence of thermal allodynia in a subgroup of patients in association with touch allodynia and paroxysmal pain also support the existence of a centralized CRPS subtype,39 although this study did not examine the contribution of CRPS duration to these findings. It is possible that CNS pathophysiology is a potential risk factor for developing CRPS in some patients. This would be consistent with prospective studies suggesting that elevated central sensitization as indexed by more severe pain intensity41 and elevated temporal summation to pain during QST7 predicts development of CRPS following tissue trauma. The higher prevalence of CRPS following minor injury in the centralized group compared with the peripheral inflammation group or mixed group in the study by Dimova et al.18 also provides some support for this. However, one cannot exclude the possibility that differences in samples and how duration was estimated (pain or disease) in the studies may explain why a link with CRPS duration was found in some but not other studies. Differences in findings between the studies may also arise because of differences in whether the statistical analyses or between-group analyses performed were correlational.Other studies outside of this review have also found evidence for disturbances in central endogenous pain inhibition in CRPS,18 is in line with the link between greater muscle hyperalgesia and motor impairments (dystonia severity and poorer finger tapping performance) in one of the other studies,51 and together,they suggest that circuitries mediating nociception may play a role in impaired motor control/dystonia in CRPS, perhaps through both peripheral and central sensitization. These findings are also in line with findings that motor cortex stimulation may alleviate chronic pain in CRPS and other pain conditions.43 However, this will need to be investigated further because patients with and without dystonia did not seem to differ in terms of widespread muscle hyperalgesia.52The presence of motor disturbances together with allodynia in the centralized CRPS group38 Other studies have also reported impairments in cognitive processing related to tactile and emotional decision making in small samples of CRPS patients36 who were unrelated to pain duration or psychological distress,2 but these latter studies did not address the presence of a possible CRPS subtype reflecting these impairments.36 Thus, more research is needed into a possible cognitive impairment subtype in CRPS. Whether and how impairments in cognition may relate to the other signs of CNS pathophysiology or CRPS outcomes remain to be investigated, but it is well documented that patients with CRPS may experience cortical changes in brain areas associated with somatosensory and motor processing,50 which could potentially interfere with cognition.32Limited evidence from one study was also found for a cognitive impairment CRPS subtype, which appeared to be unrelated to pain intensity or CRPS duration and widespread limb involvement.57 Factors that seemed to distinguish people with poor outcome from the remaining patients were a cold upper extremity CRPS limb with an initiating event other than a fracture rather than CRPS duration.54 Neurological symptoms, including hyperpathia, allodynia, dystonia, tremor, and muscle cramps, were furthermore argued to always be present in patients with severe CRPS refractory to treatment.57 However, the latter study had a high risk of bias, and thus, this will need to be replicated in a larger controlled study. Whether such changes reflect a distinct CRPS subtype remains to be determined.The fact that some mechanisms contribute to severe disease in a subgroup of patients independent of disease duration was supported by a number of the included studies.54 It has been speculated whether there is an overlap between cold CRPS and persistent CRPS as a number of studies found patients with a cold limb to have a longer pain duration than those with warm CRPS30 and signs of central sensitization,54 although some patients were found to have a cold limb in the early CRPS stage.9 Similarly, warm CRPS has been postulated to overlap with acute CRPS.27 The finding in one of the included studies that mast cell numbers were increased in affected skin from patients with acute CRPS and that this correlated with a warmer CRPS limb provide some support for this.4 Mast cell degranulation releases a range of inflammatory mediators such as tryptase, proteases, histamine, and cytokines.24 The link between acute and warm CRPS may be explained by histamine-induced vasodilation. Nonetheless, there does not seem to be enough evidence yet to fully confirm the overlaps between persistent/cold and early/warm CRPS, but the evidence points to cold and warm CRPS and acute and persistent CRPS as relevant subtypes.Besides a poorer clinical prognosis, the included studies together suggest that the cold CRPS subtype may differ from patients with the warm CRPS subtype by more often having serious life events, other chronic pain disorders, CRPS-related dystonia, sensory loss to QST in the CRPS limb, and more pain from electrical stimulation, whereas warm CRPS predominately experienced mechanical hyperalgesia in the CRPS limb.9 and greater thermal hyperalgesia to heat in warm/acute than in cold/persistent CRPS are also consistent with peripheral sensitization of heat-sensitive C-fibers during inflammation in warm CRPS.30 Nonetheless, no differences in the proinflammatory cytokines TNF-alpha and interleukin-6 in the CRPS limb was found between warm and cold CRPS.19 Conversely, bisphosphonates were found to have the best effect in early warm CRPS, and as bisphosphonates have been shown to have anti-inflammatory effects, for instance, in rheumatoid arthritis,32 this may provide support for inflammation in early warm CRPS. It is possible that different definitions used for warm vs cold CRPS may explain differences in findings because no consensus has been reached on how to define warm and cold CRPS. Such definitional issues warrant systematic examination in future research.Some have speculated whether cold and warm CRPS differ in terms of inflammation, but the evidence regarding this is unclear. A cluster analysis of signs and symptoms of inflammation provided support for a greater involvement of inflammation in warm CRPS,18 A peripheral inflammation subtype emerged based on signs of CRPS.18 Interestingly, a minority of these inflammation subtype patients experienced cold CRPS, which provide some support for inflammation being primarily present in the early warm CRPS. Furthermore, in the study of plasma cytokines, chemokines, and their soluble receptors by Alexander et al.,1 2 clusters of patients emerged: one with levels similar to healthy controls and another with elevated levels of almost all analytes. Tumor necrosis factor-alpha appeared to be important for this clustering and may be relevant to CRPS subtyping efforts. There was no difference in duration and severity between the 2 clusters, arguing against inflammation as something primarily present in acute CRPS. However, within the elevated TNF-alpha group, plasma levels of TNF-alpha seemed to increase with disease severity/duration. Unfortunately, Alexander et al.1 did not look at the contribution of warm vs cold CRPS subtype characteristics as to how they may have related to TNF-alpha patterns. Consistent with the finding that TNF-alpha levels may change in some patients with disease duration, one of the other studies found increased TNF-alpha and IL-6 immunostaining on keratinocytes in affected skin  to be more frequent in patients with acute than chronic CRPS.4 The opposing directional relationship between TNF-alpha and disease duration in the 2 studies may arise due to methodological differences (plasma vs skin biopsy) or the dissimilar subgroup focus . Studies that have investigated both local (skin biopsies or suction blister fluid) and systemic  levels of cytokines, including TNF-alpha in CRPS, have found local but not systemic proinflammatory cytokine increases.35 Future studies should assess the relationship between local and systemic cytokine levels and their relation to disease duration and severity in CRPS. The finding that MMP-2 and MMP-9 enzymes known to be involved in inflammation are differentially expressed depending on the presence of trophic changes and disease severity in one of the included studies,25 provide further support for an inflammatory subtype that is more severe, but this was unrelated to CRPS duration.Although it is unclear whether inflammation contributes to differences between the warm and cold CRPS subtypes, there is considerable evidence to suggest the involvement of inflammation in a subgroup of patients with CRPS.Future studies should attempt to discern whether warm, acute, and inflammatory subtypes reflect the same subtype and if so, determine the optimal criteria for categorizing these patients. One may expect an objective mechanistic marker such as a biomarker of inflammation to be a better indicator than the more arbitrary marker of pain duration. Similarly, studies should look into whether there is an overlap between centralized and chronic cold CRPS and, if so, whether there is an objective mechanistic marker for this subtype.Finally, evidence was found for a heritable component playing a role in a subgroup of patients with CRPS  and that this may contribute to a more severe and earlier onset CRPS , but this will need to be investigated further.11 highlight that the diagnostic criteria used may substantially change the findings and conclusions drawn. Thus, substantially more research is needed using current IASP diagnostic criteria to draw any firm conclusions about subtypes of CRPS. We took a systematic approach to covering the literature regarding subtypes but cannot rule out that some studies may have been omitted because we were unable to discern from the title or abstract that subgroups were analyzed. Furthermore, we had to rely solely on the information reported in the studies reviewed, which sometimes lacked data regarding patient characteristics.This was the first review to systematically investigate the evidence for subtypes in CRPS. We were able to identify a small number of relevant studies. The studies approached the investigation of subtypes in CRPS in very different ways, and most had a low risk of bias but with small samples. Furthermore, the same diagnostic criteria were not used in all studies. Findings of de Boer et al.22 Whether phenotyping CRPS patients into the identified subtypes has clinical relevance for predicting treatment outcome is yet to be determined. We recommend that future interventional studies examine the subtypes identified in this review because they are likely to impact on the responsiveness to treatments evaluated, and we recommend that future interventional studies seek to identify the phenotypic characteristics of treatment responders regardless of whether these characteristics fit within these identified subtypes. This is also a recommendation put forth in the ACTTION guide to clinical trials of pain treatment by the International Association for the Study of Pain.10Notably, only one of the studies was an interventional study.It is important conceptually to keep in mind that the subtypes described in this review may not be completely distinct from one another, which may complicate phenotyping. It is possible that the subtypes of CRPS may overlap within individual patients or coexist on different continuums within a patient. Nonetheless, the hope is that establishing clinically relevant subtypes may support identification of more effective treatments for CRPS within a precision medicine context. In other words, conducting clinical trials focused on a priori subtypes believed to reflect mechanisms, likely to respond to the presumed intervention mechanisms, may lead to success in clinical trials even where trials in large heterogeneous CRPS samples have failed.The authors have no conflict of interest to declare.


In this bibliometric analysis, we investigated the top 100 most cited articles on rhytidectomy, a prevalent cosmetic surgical procedure in the United States of America. Using data from Web of Science spanning from 1900 to 2021, we found these papers collectively cited 7737 times, with individual citation counts ranging from 277 to 37 (mean 77). Notably, the majority of these papers (58 out of 100) were categorized as Level of Evidence 5, indicating a prevalence of expert opinions, anatomical studies, and narrative reviews. Interestingly, none of the papers achieved Level 1 status, underscoring a lack of high-quality research in the field. The primary focus of these papers was on operative techniques (48 papers) and surgical anatomy of the face (20 papers). Only 10 articles incorporated patient-reported outcome measures (PROMs), but none utilized validated scales. This analysis highlights the urgent need for improved research methodologies in rhytidectomy studies, emphasizing the necessity for rigorous, high-quality research, and the implementation of validated rhytidectomy-specific PROMs. Rhytidectomy, or facelift surgery, is the mainstay of facial rejuvenation and is among the top 5 cosmetic surgical procedures performed in the United States of America.4 Thus, bibliometric analysis facilitates both qualitative and quantitative evaluation of published literature, providing unique insights into influential publications within a given field.Bibliometric analysis provides perspective on the growth and impact of scientific literature, when combined with citation analysis, outlines the productivity, and impact of the published material.3 However, no further work was done to characterize the contents of these broad thematic clusters. Additionally, previous bibliometric analyses of the general plastic surgery literature have revealed low use of validated objective cosmetic outcome measures5 and low levels of evidence.5-8 The quality of the most cited rhytidectomy literature remains uncertain, so we hypothesized that similar trends may exist. Therefore, our goal in undertaking this bibliometric analysis of the peer-reviewed literature was aimed at building upon the work of Honeybrook et al3 by discerning and defining the trends, characteristics, and quality of the top 100 most cited articles.A previous bibliometric analysis of the rhytidectomy literature through K-means clustering, a machine-learning approach, defined 2 keyword clusters: “surgical outcomes and techniques/approaches” and “study design.”A literature search of all journals and years (1900-2021) available on the online database Web of Science  was performed on November 25, 2021. Searching the terms “facelift” and “rhytidectomy,” the “topic” search yielded 1891 articles.The 1891 papers were subsequently sorted by “times cited” in descending order. Articles with an identical number of citations were distinguished by the mean number of citations per year, with more recent papers achieving a higher ranking. Two independent reviewers (coauthors A.D. and A.P.D.) screened the titles and abstracts of papers to compile the list of the 100 most highly cited papers directly relevant to rhytidectomy. Discrepancies were resolved by discussion with the senior author (A.K.), with review of full-text publications to settle any remaining doubts. One hundred and forty-six papers were screened to compile the list of 100 most highly cited articles on rhytidectomy for inclusion. A.d. and A.P.D.), and included: article title, authors, year of publication, journal source, total citations, mean citations per year, study design, study setting, funding status, level of evidence (graded as per the Oxford Centre for Evidence-Based Medicine [OCEBM] system [2011]),9 main research theme, and the use of clinical, cosmetic, and patient-reported outcome measures (PROMs). The extracted data were entered into a standardized computer spreadsheet .Data extraction from full-text articles was independently undertaken by 2 authors  featured predominantly on the list compared with multicenter designs (n = 2). Both multicenter studies originated in the United States of America, which produced the highest output of papers overall (n = 75). This was followed by Australia (n = 5), then the United Kingdom  contributed the most papers (n = 72 papers), with the remaining journals contributing <10 papers each  and facial anatomy (n = 20). One paper predominantly focused on male rhytidectomy (n = 1).11Rhytidectomy technique was the main subject in a significant proportion of papers n = 48; . Other pn = 58), representative of the large majority of expert opinion papers (n = 29), anatomic/cadaveric (basic science) studies (n = 18), and narrative reviews (n = 11). Nineteen papers achieved Level of Evidence 4, while 13 achieved Level of Evidence 3, and 10 achieved Level of Evidence 2. No papers on the list attained Level of Evidence 1 . No papers reported validated subjective or objective cosmetic outcome measures.To the best of our knowledge, this bibliometric analysis is the first of its kind to review and classify the highest cited rhytidectomy literature according to OCEBM methodological quality. Although studies largely failed to achieve the highest levels of evidence, the widespread adoption of subjective outcomes highlights the necessity of eliciting postprocedural patient satisfaction in the context of rhytidectomy outcomes.3 Machine learning has increasingly been applied in bibliometric analyses due to its scalability, open-access nature, and ease of use.13 However, limitations include inaccurate classification and poor model performance due to overfitting—a common phenomenon associated with machine learning use wherein the model learns the training data too closely and therefore when presented with new data, does not work as well.13 Therefore, this bibliometric analysis used traditional systematic review methods and extracted data from full texts, rather than abstracts, to provide a more comprehensive, accurate outline of impactful rhytidectomy research.This bibliometric analysis builds upon previous work, which used a machine-learning approach to derive topic trends for rhytidectomy abstracts through K-means cluster mapping.6 Importantly, PROMs were lacking and overall levels of evidence were low.6 This is exemplified by the highest cited article in this analysis, studying the relevance of facial soft-tissue anatomy to the age-related stigmata of facial aging and rhytidectomy. Through fresh cadaver and intraoperative dissections, Stuzin et al10 characterized the arrangement of facial soft-tissue architecture into a series of concentric layers and determined the relationship between the superficial and deep facial fascias. Building upon description of the superficial musculoaponeurotic system (SMAS) by Mitz and Peyronie,14 the authors meticulously outlined the relationship of the SMAS to other facial structures and carefully described SMAS mobilization technique to minimize the risk of facial nerve injury.10 They also reported on the soft-tissue ligamentous support system of the face and its attenuation with aging.10 Although the paper is considered the anatomic basis of the “modern” facelift, as a cadaver study, the level of evidence was low, and there were no direct clinical or subjective outcomes relevant to the rhytidectomy procedure. Nevertheless, facial soft-tissue anatomy featured prominently in many of the other highly cited papers. Arguably, repositioning of these structures has been the most impactful on visual outcome of the face following rhytidectomy.15Broadly, our findings are representative of general trends across academic plastic surgery, whereby highly cited articles were mostly single-center, US-based, and published in PRS.16 Authored by Hamra in 1992, the second most highly cited article elaborately describes the composite rhytidectomy technique.17 Building upon the standard SMAS facelift, Hamra refines his own description of the deep-plane rhytidectomy technique to address formation of the malar crescent caused by progressive orbicularis oculi ptosis in the aging face. In this paper, pioneering repositioning and fixation of the orbicularis oculi muscles in conjunction with en bloc repositioning of the SMAS, cheek fat pads, and cervical platysma in their original relationship with the overlying skin as a musculocutaneous flap in the deep-plane rhytidectomy technique, forms the hallmark of the composite facelift procedure.17 Hamra's technical quest to achieve a more natural and youthful appearance than the standard SMAS facelift gained acceptance and eminence.Increased understanding of anatomical soft-tissue alterations contributing to facial aging has allowed the development of techniques to combat the specific anatomy leading to an aged appearance of the face.18 Written by Hamra in 1990, the technique preceded description of his composite rhytidectomy, and instigated novel inclusion of the malar fat pads into the facelift procedure.18 Differing from the SMAS lift originally described by Skoog in 1974,19 the operative technique in deep-plane rhytidectomy has been widely regarded to produce superior outcomes in the improvement of prominent nasolabial folds.18 While this likely accounts for the high citation number achieved, the procedure conferred a slightly higher risk of facial nerve injury,18 which may also partly explain the total number of citations.The third most highly cited paper, entitled “The deep-plane rhytidectomy” elegantly describes an approach to target redundant laxity of the nasolabial folds.20The top 100 articles broadly capture the evolution of surgical rejuvenation techniques in the rhytidectomy procedure, from skin tension only techniques focusing on a variety of dissections and fixation planes , to commonplace repositioning or filling of deeper tissues prior to skin tightening and resection, and greater endeavors in combatting frequent sequelae of the “traditional facelift” such as optimization of tissue elevation vectors in a more anatomical vertical direction targeting “lateral sweep” and consideration of arcus marginalis release and orbital fat preservation  in periorbital rejuvenation minimizing “hollow eyes.”21 entitled “The medical facelift,” endeavored to evaluate the function of novel tissue tightening technology on facial skin laxity through the use of nonablative radiofrequency. Presenting a case series, the authors reported that nonablative radiofrequency technology is a safe and effective method to achieve tissue tightening of the face to correct excessive sagging, with the benefit of shorter downtime compared with traditional surgical rhytidectomy. Although ablative and nonablative resurfacing principles may result in improvements to the skin surface, adequate lifting of underlying ptotic tissues, crucial in achieving a youthful facial appearance, is not attained.22 Accruing 85 citations, this paper is likely representative of the peaked interest in minimally invasive approaches to facial rejuvenation.Illustrated through several prominent highly cited articles featuring on the top 100 list, the quest for a more durable and less invasive means of facial rejuvenation has driven pursuit of procedures considered as alternatives to rhytidectomy and led to the development of ancillary concepts. One such paper by Ruiz-Esparza and Gomez,22-24 Although experts possessing an artistic touch may report pleasing results, the concepts in these procedures may result in unnatural contours with increased facial volume and visible center of gravity shifting to the lower third of the face.22 Such papers provided low contributions to the top 100 list, perhaps as such techniques are featured on newer emerging papers which generally are not cited until 1 to 2 years postpublications, with peak citation count at 3 to 10 years postpublication25 and therefore may not have yet accrued enough citations for inclusion within this bibliometric analysis.Several further types of nonsurgical interventions and ancillary concepts have been described including injections with a variety of gels or autologous fat transfer through lipofilling.27 Together with traditional rhytidectomy incisions, suspension techniques are generally used to achieve better results and can be performed with autologous tissue, such as tendons or fascia, or prosthetic materials, including sutures, slings, or mesh.28 Among the many suspension techniques, subcutaneous suspension using SMAS as the fixation basis, with posterolateral vector tissue elevation, and subperiosteal detachment followed by en-bloc repositioning of structures using a purely vertical vector are concepts most widely developed.29 Suspension techniques have also been utilized to reposition and anchor the facial soft tissues to the temporal fascia or the periosteum in minimally invasive endoscopic procedures of the middle and lower facial thirds.30 Yet, there is a paucity of information in existing literature regarding efficacy, safety, durability, and possible complications of current clinical practices.26The passage of sutures under the skin of the face and neck, utilizing threads in facelift procedures to compensate for redundant tissue sagging and flaccidity is not a new idea and can avoid large incisions and reduce recovery time.32 Therefore, reducing operative risks in rhytidectomy by adopting methods for safe practice is a necessary prerequisite.32 Only 12 out of the 100 most cited papers focused on such specific complications and their prevention. Postrhytidectomy, hematoma remains the most common complication, often occurring within the first 24 h after the procedure.31-34 Hematoma formation has been significantly associated with neck undermining, systolic blood pressure, male gender, nonsteroidal anti-inflammatory or aspirin intake, and smoking. Hematoma may lead to prolonged facial swelling, skin necrosis, and even the potential for airway compromise.31-34 Adjuncts such as compressive dressings, drains, and fibrin glue have been tried to reduce the incidence of postrhytidectomy hematoma, though results have been mixed and often not statistically significant.35 However, the exclusion of adrenaline infiltration has been shown to significantly reduce hematoma formation requiring surgical evacuation, without change to the incidence of any other facelift complications.35 Though the paper by Grover et al showed the effectiveness of omitting vasoconstrictors in reducing hematoma, it has not been universally accepted as most surgeons prefer the “dry” field afforded by vasoconstrictors and hypotension.34In any elective cosmetic procedure, a serious complication, even when rare, is deemed unacceptable.11 Compared with the rhytidectomy procedure in females, the male rhytidectomy technique must follow a different approach throughout the surgical course for the preservation of hair follicles, restoration of a masculinized youthful appearance, and reduction of hematoma risk.36 This is comprehensively outlined by a single paper on the most cited list that predominantly focused on male rhytidectomy.11 The authors reported an increased incidence of large hematomas in male patients compared with females11; a finding that has since been confirmed.26 Interestingly, stringent perioperative blood pressure control has demonstrated reduced hematoma incidence in male patients,37 yet, not to a level comparable to or lesser than postrhytidectomy hematoma formation incidence in females.37 Further work is required to examine male-specific risks and complications, in addition to the incremental characterization and refinement of the male rhytidectomy surgical procedure.Although predominantly a procedure sought out and undertaken by females, more men are electing to undergo rhytidectomy than ever previously.38 Comparing facelifting techniques between lateral and standard SMAS facelifts with extended SMAS and composite rhytidectomies, Ivy et al39 featured on the top 100 list and presented a prospective study randomizing separate halves of 21 patients’ faces, 19 undergoing primary rhytidectomy. Although patients were followed up for 1-year postprocedure, with postoperative photographs taken at 6 and 12 months, the descriptive nature of outcomes presented, subjective comparison of postoperative photographs, and lack of PROMs render facilitation of comparison and evaluation between techniques challenging and complex. Interestingly, a retrospective cohort study also included in the list, undertaken by Kamer and Frankel40 comparing the tuck rate between SMAS rhytidectomy vs deep-plane rhytidectomy found that a tuck was required 71% less frequently following a deep-plane facelift than after a SMAS lift, although all rhytidectomies in the study were performed by 1 single surgeon and the authors acknowledged that a tuck procedure cannot reliably imply a less than optimal facelift in all cases. Recognizing variability among surgeons as an impeding factor in the comparison of facelifting techniques, the authors also highlighted the difficulty posed by factors such as the highly subjective nature of aesthetics, differences in patient anatomy, and specific patient desires.40Currently, a multitude of techniques are utilized for performing facelifts, yet there is no clear consensus as to which, if any, of these techniques may be most effective.41 Since its inception to date, only 2 of the top 100 most highly cited papers accrued sufficient citations to be included on this list. Perhaps, in part, the lack of PROMs may be attributable to newer papers with lesser citations.25 Without reference to validated patient satisfaction indicators, it has been argued that clinical outcome measures are inadequate.41 Evaluation of PROMs is an urgent area requiring improvement in the rhytidectomy literature41 and clinical practice.42Although 10 papers in this bibliometric analysis reported PROMs, not surprisingly, none incorporated validated patient-reported outcomes. FACE-Q, the first validated PROM designed to measure a range of important outcomes for facial aesthetic surgery patients and developed for use in rhytidectomy alongside other facial aesthetic procedures was published in 2013.41 particularly important in rhytidectomy and other cosmetic procedures where appropriate patient selection is paramount.42 The collection of clinically meaningful data regarding aesthetic procedures through utilization of specific, valid, and relevant PROMs has been recommended by the American Society of Plastic Surgeons.43 Similarly, the routine reporting of PROMs preoperatively and postoperatively in facial aesthetic procedures including rhytidectomy has been advised by the Royal College of Surgeons in the United Kingdom44 and perhaps these proposals should be mandated in journals publishing research related to rhytidectomy.Crucial for facilitating informed consent, shared decision making, patient choice, and benchmarking quality improvement in services, PROMs can help identify where surgical intervention in patients may be less likely to be of benefit,45 and form possible limitations to this study. In-house review and author self-citation can result in an unconscious bias in addition to English language and national biases. Bandwagon bias, powerful person bias, and bias by omission are examples of conscious biases that can occur in attempts to attain a competitive publication edge. Therefore, automatically assuming that highly cited articles possess greater significance can result in incorrect conclusions. Instead, individual assessment of each article is recommended to critically appraise robustness of study methodology and formation of paper conclusions. Additionally, as cornerstone articles in rhytidectomy become accepted as assumed knowledge and therefore accrue lesser citations, they can become subject to obliteration by inclusion,46 which may provide an explanation for the absence of certain papers from this analysis.Bibliometric analyses are subject to various potential inherent biases that have previously been well summarized25 Nonetheless, citation frequency analysis has been recognized as a valid measure of evaluating research that is relied upon and assimilated by the scientific community within the specified field. The top 100 articles presented in this bibliometric analysis are considered immensely influential to the advance of modern-day practice in rhytidectomy, although other relevant papers that accrued lesser citations are likely to have been omitted. Nevertheless, this list, yielded by a comprehensive literature search, provides an excellent introduction to the classical rhytidectomy works. This bibliometric analysis provides a broad overview and historical perspective on pertinent topics gaining prominence, as well as highlighting deficiencies in studies’ methodological quality.Citation frequency analysis should be carefully interpreted when evaluating individual papers and study authors, with caution given to the aforementioned limitations.38 Although most surgeons have a “favorite” technique, collectively, the surgical community is limited by a lack of definitive data, facilitating the objective comparison of individual techniques.47 The various identical twins’ studies reported by Alpert et al,48 Antell et al,49 and Antell and Orseck50 further add that we lack compelling evidence that 1 technique is better than another. Increasing interest in ancillary concepts, such as lipofilling and other nonsurgical facial rejuvenation techniques, combined with the rhytidectomy procedure or as stand-alone alternatives to surgical facelifting, adds a further dimension and increases the complexity of technical and outcome-based comparison of facial rejuvenation. Higher quality evidence evaluating clinical and patient-reported outcomes through robust tools, such as FACE Q, is required to bring in higher level studies into the rhytidectomy literature forming a solid basis for evaluation of the various techniques.Despite market demands, social media trends, and ancillary procedures, the individual surgeon's preferred facelift technique has largely remained unchanged. We can speculate whether this reflects the surgeon's comfort level and satisfaction with a particular technique or is it, as we have presented here, that there is a lack of compelling evidence of 1 procedure over another.This extensive bibliometric analysis comprehensively examines the top 100 most highly cited papers in rhytidectomy and shows the evolution in the field over the past 6 decades. A multitude of refinements, safety considerations, and developments in rhytidectomy techniques are highlighted. Improvements in the quality of rhytidectomy literature must be sought by active prioritization of the publication of methodologically robust studies with higher OCEBM levels of evidence, such as well-designed randomized controlled trials or observational analytic studies. Furthermore, the adoption of validated PROMs designed for rhytidectomy is centrally important and crucial for aligning patient satisfaction with clinical outcomes and providing high-quality evidence-based patient care.ojad099_Supplementary_DataClick here for additional data file.


Dear Editor1. Research collaboratives have become a pivotal part of delivering high-quality patient-centred research. Professor Björck highlights several points that we would like to respond to.We read with interest the Gloves Off opinion piece by Martin Björck on research collaborativesThe author begins by focusing on fraudulent publications, highlighting that co-authors of Paolo Machiarini may regret adding their names to manuscripts which subsequently turned out to be fabricated. We would argue that the committee-based leadership model of research collaboratives, where decisions and tasks are attributed to a collective body of researchers rather than to a specific individual, actually protects against such issues. In a study in which research data originate from tens or hundreds of institutions and are processed by a core research group that assumes overall responsibility, it is difficult to see how any one rogue individual could significantly corrupt the meaning or interpretation of the collaborative effort.2. It is unfortunate that the authors of the guideline did not contact the Vascular and Endovascular Research Network (VERN). If they had, we would have directed them to the publication that discusses patient presentations and outcomes (tier 2 of the COVER study)3, rather than the publication that Professor Björck cites, which discusses service reconfiguration during the pandemic (tier 1 of the COVER study). The tier 2 publication presents data regarding patients presenting with ALI, with those undergoing revascularization having an in-hospital mortality rate of approximately 20 per cent. We would also have been able to share significant as-yet unpublished raw anonymized data, including longer-term outcomes of patients in tier 2 of the study (paper in preparation). VERN has shared such data with other guideline committees in Europe when approached . As Professor Björck points out, research takes time, and we feel it unrealistic to expect data on 1-year outcomes of patients treated during the first pandemic wave to be in the public domain only 18 months after the start of the pandemic.Professor Björck then discusses the COVER (COvid-19 Vascular sERvice) study, stating that the authors of the European acute limb ischaemia (ALI) guidelines failed to find mention of ALI in one of the publications originating from that studyTrainee collaboratives exist in a plethora of fields now, delivering high-quality studies such as the large-scale BLUEBELLE and ROSSINI RCTs. The international COVER study was set up and delivered by VERN within the space of a few months. It would not have been possible to deliver this time-sensitive global effort without the help of a research collaborative of this magnitude, and once again we would like to formally thank our colleagues from over 50 countries around the world who contributed to COVER.Before COVER, VERN had already demonstrated its utility by delivering several successful high-quality prospective projects, which have been multiply cited, including within national and international guideline documents, thus directly influencing patient care. These include the GIVE (Groin wound Infection after Vascular Exposure) study, which has resulted in the publication of several important pieces of work highlighting the persistently high incidence of groin wound infection in vascular surgery, identifying key risk factors affecting incidence, and developing a risk calculator that demonstrates significantly better performance in predicting this outcome compared with previous efforts. VERN is currently involved in five prospective studies being delivered across the National Health Service and internationally  on topics as diverse as diabetic foot attack, trauma with vascular injury, acute aortic syndrome, frailty, and major lower limb amputation. We look forward to sharing the results of these exciting studies in due course.Vascular and Endovascular Research Network (VERN) Executive Committee: Graeme K Ambler , Louise Hitchman , Ruth A Benson , Panagiota Birmpili , Robert H J Blair , David C Bosanquet , Nikesh Dattani , George Dovell , Brenig L Gwilym , Katherine Hurndall , Matthew Machin , Sandip Nandhra , Sarah Onida , Joseph Shalhoub , Aminder A Singh , Athanasios Saratzis .Disclosure. The authors declare no conflict of interest.


Aspergillus-derived mycotoxins in the feed and food chain”, we decided to re-open this chapter to collect additional and comprehensive information on Aspergillus mycotoxins. The major topics discussed earlier covered almost every aspect of mycotoxin research in this exceptionally important field, concentrated in 20 significant research and review papers  the assessment of aflatoxin risks and the newly emerging mycotoxin removal techniques, which will hopefully be suitable for the treatment of the unfavorable trends observed in Europe recently due to the climate change, (ii) the rise of non-aflatoxigenic Aspergillus flavus-based biocontrol technologies gaining ground in sub-Saharan African countries, (iii) fine-tuning of mycotoxin biosynthesis at the level of transcription factors, and (iv) interference of mycotoxins with the normal physiological processes of liver and kidneys. We are pleased to recommend all these new publications to all professionals, university lecturers, students and other interested parties who want to get a comprehensive, authentic picture of the latest results and future trends related to Aspergillus mycotoxin research.Owing to the outstanding success of the previous Frontiers in Microbiology Research Topic titled “Aspergillus species are moving constantly north in Europe due to the climate change, which is an emerging threat to consumers. Advanced mycotoxin control and disinfection techniques are required to combat successfully such molds and their dangerous metabolites. Although effective techniques are available we need to explore their limitations to facilitate the development of future tools to address the growing world-wide aflatoxin risk adequately .Today it seems unquestionable and irreversible that aflatoxigenic Farkas et al.).The first large-scale survey of chronic aflatoxin M1 (AFM1) exposure of Hungarian consumers showed that AFM1 exposure of older age groups does not pose an emergent health risk, but younger age groups, especially toddlers, are exposed to a certain level of health risk. Further studies are awaited to provide a more detailed overview of the true aflatoxin health risk and exposure assessment of combined multi-mycotoxin contamination .Lactic acid bacteria have always been considered among the promising microorganisms in inhibiting the growth and toxin production of mycotoxin-producing molds. Latest results reached by the probiotic Aspaergillus strains to control aflatoxigenic molds in Europe as well although there are still concerns about applying such agents in our continent . Imporatntly, highly effective Aflasafe® products have been developed, authorized or approved in many sub-Saharan African countries. Most recently, the distribution of aflatoxin contamination was mapped and the causal agents were identified in Burundi. Furthermore, some atoxigenic genotypes of Aspergillus flavus were detected across the country and four non-aflatoxigenic strains were selected as ingredients of the new biocontrol product Aflasafe BU01 . In addition to country-specific atoxigenic genotypes, registered ingredients of the Kenyan biocontrol product Aflasafe KE01 also frequently appear in maize and groundnut produced in Burundi, carrying the possibility that Aflasafe KE01 could be used across East Africa . In Nigeria, the biocontrol agent Aflasafe produced by the private sector has been shown to be effective in meeting the aflatoxin tolerance threshold in maize. These findings were presented and discussed at a National Workshop attended by all parties interested in ensuring strict and effective control of aflatoxin in the Nigerian food chain .It is an attractive idea to develop and use atoxigenic Loi et al.). In the filamentous fungus model organism Aspergillus nidulans, interactions between the bZIP-type transcription factors AtfA and AtfB are likely when genes involved in stress tolerance, sexual and asexual developments as well as secondary metabolite  production are co-regulated by them. It is noteworthy that no sterigmatocystin production was observed in agar plate cultures of the A. nidulans ΔatfA gene deletion mutant meanwhile the ΔatfB mutant and the ΔatfA ΔatfB double mutant produced this mycotoxin nearly at wild-type level .A deeper understanding of the genetics of mycotoxin production is of paramount importance e.g., when novel, RNA interference-based, plant host induced control technologies are developed .The adverse effects of mycotoxins can be observed in several organs of both humans and domestic animals but liver and kidneys are particularly sensitive. Hepatic enzymes are key players in the metabolism of these toxic compounds, which is divided into Phases I  and II (conjugation). In humans, phase I metabolism is mainly performed by cytochrome P450 (CYP450) enzymes, among which CYP1A2 and CYP3A4/3A5 enzymes contribute to the metabolism of AFB1 at 49 and 45%, respectively, as determined in pooled human live microsomes. The 2-microglobulin (β2-MG), N-acetyl-β-D-glucosaminidase (NAG), kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) should also be monitored in mycotoxin-exposed livestock as in pigs, which are particularly susceptible to Aspergillus-derived mycotoxins .Although kidneys are also remarkably vulnerable to the adverse effects of mycotoxins, farm animals are not generally screened yet for mycotoxin induced nephropathy. We suggest that changes in urinary biomarkers extensively used in environmental toxicology including βAll authors served as co-editors to the Research Topic and also contributed to, critically read, discussed, and approved this editorial.


CXCR5 is involved in seizures via an unknown mechanism. Here, we first determined the expression pattern and distribution of the CXCR5 gene in the mouse brain during different stages of development and the brain tissue of patients with epilepsy. Subsequently, we found that the knockdown of CXCR5 increased the susceptibility of mice to pentylenetetrazol- and kainic acid-induced seizures, whereas CXCR5 overexpression had the opposite effect. CXCR5 knockdown in mouse embryos via viral vector electrotransfer negatively influenced the motility and multipolar-to-bipolar transition of migratory neurons. Using a human-derived induced an in vitro multipotential stem cell neurodevelopmental model, we determined that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton during various stages of neurodevelopment. Electrophysiological experiments demonstrated that the knockdown of CXCR5 induced neuronal hyperexcitability, resulting in an increased number of seizures. Finally, our results suggested that CXCR5 deficiency triggers seizure-related electrical activity through a previously unknown mechanism, namely, the disruption of neuronal polarity.Epilepsy is a common, chronic neurological disorder that has been associated with impaired neurodevelopment and immunity. The chemokine receptor The online version contains supplementary material available at 10.1007/s12264-023-01087-w. CXCR5 functions in cell migration and localization and coordinates intercellular interactions ). To explore why the knockdown of CXCR5 in cortical neurons leads to higher susceptibility to epilepsy, we tested neuronal excitability using whole-cell patch-clamp recording in neurons in vitro, and found that the resting membrane potential was unaffected  ted Fig. H, K. Howncy Fig. L and chancy Fig. J, L. ThiCXCR5 and epilepsy, we performed drug rescue experiments both in vivo and in vitro. We found that the addition of jasplakinolide alleviated the impairment of neuronal migration when CXCR5 was knocked down, resulting in increased upward migration of neurons from the lower CP region, with more neurons detected in the upper CP  acute epilepsy models, in which a chemical (such as PTZ), an acoustic source, or an electrical stimulus, is applied; and (2) chronic seizure models, in which KA or trichothecene are applied to induce SRSs following the structural damage caused by sustained SE , 27. As via asymmetric division of radial glial cells and migrate along the radial projections of glial cells toward specific regions of the peripheral cortex during the late stage of cerebral cortex development [CXCR5 during the longitudinal migration of cortical neurons from the SV/SVZ region to the upper CP in late gestation results in multipolarity and disturbed direction of migration, with most of the cells staying in the SVZ. This evidence suggests that CXCR5 deficiency causes a disorder of neuronal migration in the late embryonic period.The normal functioning of the nervous system depends on its conventional structural development. In the mouse embryo, most cortical neurons  are born in the VZ elopment . Our expCXCR5 on neuronal polarity, we performed in vitro cell culture experiments based on a neurodevelopmental model of human-derived iPSCs [CXCR5 deficiency affects epilepsy by contributing to impaired neuronal migration during the embryonic period. However, animal models of neurodevelopment cannot fully replicate the human condition [CXCR5, the axial dendrites of neurons exhibited impaired development compared with the control group at week 4 of induced differentiation. By week 8, a marked reduction in neuronal complexity was evident. Furthermore, we found that the knockdown of CXCR5 hindered neuronal maturation, as evidenced by reduction in total branch number and total branch length, as well as decreased dendritic spine density and impaired dendritic spine maturation. In the mammalian cerebral cortex and hippocampus, dendritic spines normally receive and integrate excitatory synaptic signals, and abnormal dendrites may lead to excessive neuronal firing. In summary, abnormal dendritic spine development can directly cause neuronal excitability and seizures. To demonstrate that these effects of CXCR5 deficiency are specific to neurons and not to other neuronal cells, we overexpressed CXCR5 under the control of a neuron-specific promoter using a viral vector. We found that the overexpression of CXCR5 led to a significant increase in the number of primary and secondary neuropil synapses in neurons at week 4, but did not exert a positive effect at week 8. These findings fully validate and complement the results obtained in vivo in mouse embryos. Our results confirmed that CXCR5 gene deficiency causes abnormal neuronal development and polarity, impairs neuronal migration in late pregnancy, and ultimately increases the susceptibility to epilepsy in adulthood. To determine how CXCR5, a G protein-coupled receptor localized on the cell membrane, affects neuronal polarity, we focused on actin proteins based on our protein profiling results. Interruption of the dynamic of F-actin/G-actin cycle leads to an imbalance in actin aggregation and depolymerization that can lead to amyloid degeneration, which is found in Down syndrome and Alzheimer’s disease. These consequences stem from the fact that actin is essential for cortical development and dendritic spine formation [shCXCR5 group, F-actin had a lower expression level and range, and the neurons showed a more naive state than that seen in the control group. We quantified F-actin by immunofluorescence and western blot with strict homogeneous control of exposure intensity and segmentation threshold; using jasplakinolide recovered abundant myofilament proteins and dendritic branches in CXCR5-deficient neurons. Our results reinforce the idea that the disruption of microtubule-based processes underlies widespread neuronal migration disorders, and further suggest that CXCR5 regulates neuronal migration and polarization by stabilizing the actin cytoskeleton.To scrutinize the effect of ed iPSCs  to simulondition , 31. Accondition  that canormation . This paCXCR5 during embryonic development is associated with seizures in adulthood. Susceptibility to epilepsy has long been thought to be related to the stability of neural networks and intrinsic neuronal electrophysiological homeostasis. Our data suggest that CXCR5 may promote the survival of abnormally excitable neurons resulting from developmental migration disorders, leading to increased epilepsy susceptibility.Our findings suggested that the knockdown of in vivo and in vitro experiments, which included behavioral experiments, in utero electroporation, cell culture, and electrophysiological experiments, demonstrated that CXCR5 deficiency during embryonic development leads to abnormal neuronal polarity, impaired neuronal migration, and increased neuronal hyperexcitability, resulting ultimately in increased susceptibility to epilepsy and seizures.In conclusion, our via which they cause epileptiform activity are unknown. Focal cortical dysplasia is estimated to be associated with 30% of cases of refractory epilepsy, but neither surgical nor pharmacologic treatment is satisfactory in these patients [CXCR5 gene-targeted therapy for refractory epilepsy.Almost all neuronal migration disorders, including anencephaly, periventricular nodal ectopia, and subcortical zone ectopia, are risk factors for seizures ; howeverpatients . FurtherSupplementary file1 (PDF 145 kb)Below is the link to the electronic supplementary material.


The incidence of patients with heart failure is growing steadily, particularly due to advancements in medical therapy. Even the sickest patients with cardiac defects that were once uniformly fatal can now be palliated well into adulthood and are expected to contribute to this growth . While hToday, left ventricular assist devices (LVADs) encompass a broad spectrum of therapy alternatives from bridge-to-transplantation to bridge-to-recovery and can be implanted with minimally invasive techniques . NeverthIn recent years, there has been a growing interest in the utilization of extracorporeal hemoadsorption techniques in cardiac surgery to mitigate the burden of dysregulated immune response by immunmodulation through the elimination of cytokines from the systemic circulation ,12,13,14In spite of the similar characteristics of end-stage heart failure or LVAD patients and patients with active infection in terms of elevated proinflammatory cytokines, elevated thrombosis and bleeding risk, hepatic and renal dysfunction, angiodysplasia, and clinical frailty with worse operative outcomes, the adoption of hemoadsorption filters at the time of LVAD surgery or during intensive care stay as an adjunct therapy to hemofiltration is limited. Besides individual clinical experience, our understanding of the potential role of hemoadsorption filters in LVAD implantation depends on, if not one, a few studies. In Zhigalov and associates’ single-institution study, in which they compared a treatment group to a matched group, patients treated with a new hemoadsorption filter (Cytosorb-Cytosorbents Europe GmbH) did not benefit in terms of survival and they were more likely to develop respiratory failure (54% vs. 30%), require mechanical ventilation for longer than 6 days (50% vs. 28%), and require more tracheostomies (31% vs. 13%) . In lighAn association between the use of hemoadsorption in cardiogenic shock patients during LVAD surgery and postoperative vasopressor support, improved hemodynamics, or accelerated lactate clearance was also not observed by Pausch and associates . Moreovep = 0.18) and 23% vs. 29% (p = 0.37)) [On the other hand, in their recent retrospective study, Haidari and associates analyzed the impact of the intraoperative use of hemoadsorption in heart failure patients undergoing LVAD implantation with cardiopulmonary bypass and reported a significant reduction in postoperative vasoplegia incidence in the treatment group. A significant early mortality difference was not observed between the matched groups with similar INTERMACS characteristics, though both the 30- and 90-day mortality rates were lower in the treatment group  intends to investigate the efficacy of Cytosorb treatment during LVAD implantation in the mitigation of postoperative vasoplegia and organ dysfunction as well as perioperative changes in IL-6 . While tAlthough the initiation of LVAD therapy has changed the fate of patients with end-stage heart failure, these patients still represent an extremely fragile population. In addition to fine-tuning the surgical technique, further research aimed at defining potential biomarkers in LVAD patients and the benefit of eliminating them from the systemic circulation through hemoadsorption is warranted. In consideration of the efficacy of cytosorbents in patients with active endocarditis or sepsis and its declared capacity to filter out cytokines such as IL-6, TNF-a, and interferon-gamma or anticoagulant drugs such as P2Y12 inhibitors or factor Xa inhibitors, its safety and feasibility in patients undergoing surgery with (a) myocarditis or active endocarditis, (b) severe hepatic or renal dysfunction and hyperbilirubinemia, and (c) in urgent need of cardiac surgery despite effective anticoagulation therapy need to be further investigated. The impact of proinflammatory cytokine filtration at the time of both LVAD and heart transplantation surgeries on the reduction of organ rejection also bears substantial potential for groundbreaking research and deserves further attention.