The study, conducted between April 1 and 15, 2026, targeted the physicians who make these split-second decisions: faculty members, pediatric intensive care specialists, and subspecialty fellows practicing across Türkiye. The investigators designed a 24-item questionnaire grounded in the existing literature and distributed it through individual messages and professional WhatsApp groups, a delivery method that reflects how clinical knowledge now travels in real time among intensivists. Electronic informed consent was obtained from every participant, and the protocol received ethics approval from the Selçuk University Faculty of Medicine Local Ethics Committee in February 2026. Seventy physicians completed the survey, and their answers paint a detailed portrait of a therapy that has outpaced its formal guidelines.

The headline number is hard to ignore. Fifty-one of the seventy respondents, or 72.9 percent with a 95 percent confidence interval of 61.5 to 81.9, reported having used methylene blue at least once during their professional careers. Perhaps more telling, this experience was evenly spread across the professional landscape: use did not differ significantly by job title, by whether the physician worked in a university hospital or another institution type, by the bed capacity of the pediatric intensive care unit, or by years of clinical experience. In other words, methylene blue is not the preserve of a handful of high-volume academic centers. It has penetrated pediatric critical care practice broadly, from large units to small ones, and among junior fellows as much as senior faculty.

What drives clinicians to reach for the dye is equally consistent. Every single respondent with prior methylene blue experience reported using it for catecholamine-resistant septic shock, the dreaded scenario in which a child in septic shock continues to deteriorate despite escalating doses of the vasopressor and inotropic drugs that normally restore blood pressure. In this state, often called refractory or vasoplegic shock, the problem is not simply a lack of circulating catecholamines but a breakdown in the vasculature’s ability to respond to them. Understanding why methylene blue might help in that situation requires a brief tour through vascular biochemistry, and it is here that the drug’s mechanism is both elegant and, in children, incompletely validated.

During severe sepsis, inflammatory cascades induce vascular smooth muscle cells to overproduce nitric oxide, a potent vasodilator. Nitric oxide activates soluble guanylate cyclase, which raises intracellular cyclic guanosine monophosphate and relaxes the muscle layer of blood vessels, causing the profound vasodilation that characterizes vasoplegic shock. Methylene blue intervenes directly in this pathway: it inhibits both nitric oxide synthase and soluble guanylate cyclase, thereby damping the cyclic guanosine monophosphate signal and restoring vascular tone. The result, when it works, is a rapid rise in systemic vascular resistance and arterial pressure, which is precisely why intensivists describe its effect as sometimes dramatic. But the same mechanism carries theoretical liabilities, including the risk of increasing pulmonary vascular resistance and reducing cardiac output in patients whose hearts cannot compensate, which is why careful patient selection matters so much.

The survey data show that clinicians have converged on a recognizable administration strategy even without a standardized protocol. The most common approach, reported by 70.6 percent of experienced users, is a bolus dose followed by a continuous infusion, a design that delivers an immediate hemodynamic effect and then maintains it. Among physicians who use a bolus, 76.2 percent prefer 1 milligram per kilogram, and among those who run an infusion, 47.7 percent favor a rate of 1 milligram per kilogram per hour. These figures suggest an emerging de facto dosing convention, but the fact that more than half of infusion users choose something other than the modal rate underscores how much individual judgment still shapes therapy. Deciding when to start the drug is equally unsettled: 45.1 percent of experienced users rely on the vasoactive-inotropic score, a composite numerical measure of the doses of vasopressor and inotropic medications a patient is receiving, to guide the timing of methylene blue initiation, while the majority use other or unspecified criteria.

Safety practices reveal even wider variation, and this is where the survey carries its most important clinical message. Methylene blue is contraindicated or hazardous in patients with glucose-6-phosphate dehydrogenase deficiency, an inherited enzyme defect that is relatively common in populations around the Mediterranean and elsewhere. In G6PD-deficient individuals, the drug can trigger hemolysis, the destruction of red blood cells, turning a hemodynamic rescue into a hematologic emergency. Yet only 21.6 percent of respondents reported routinely asking about or screening for G6PD deficiency before administering the drug. On the cardiac side, 49.0 percent said they assess ventricular function by echocardiography or point-of-care ultrasound before or during therapy, meaning roughly half do not formally evaluate whether a child’s heart can tolerate the increase in afterload that restored vascular tone imposes. These gaps are not academic; they define the difference between a monitored rescue therapy and an unmonitored gamble.

Does the drug actually work in these children? The self-reported outcomes from the survey offer a cautious but intriguing answer. A majority of experienced users, 58.8 percent, reported observing transient hemodynamic improvement after methylene blue administration, while 17.6 percent described marked and sustained clinical improvement. The remainder presumably saw little or no benefit. This distribution mirrors what small pediatric case series and adult vasoplegic shock literature have long suggested: methylene blue can produce impressive short-term gains in blood pressure, but translating those gains into survival remains uncertain, and the drug is best understood as a bridge that buys time rather than a definitive treatment for the underlying septic process. Notably, no randomized pediatric trial of sufficient size exists to confirm or refute these impressions, which is precisely the void this survey illuminates.

For the physicians who have never used the drug, the barrier is not skepticism about the science but simple unfamiliarity. Among non-users, 78.9 percent cited lack of familiarity or experience as the main reason they had not administered methylene blue, far outweighing concerns about efficacy or safety. That figure is a roadmap for intervention: educational initiatives, simulation-based training, and institutional protocols could convert a large pool of willing but untrained intensivists into confident users, ideally within a framework that standardizes the safety screening the survey found lacking. The authors conclude that their findings highlight the need for standardized protocols, educational initiatives, and prospective multicenter studies addressing methylene blue use in pediatric refractory shock, a three-part prescription that addresses knowledge, practice, and evidence in turn.

The broader significance of this study extends beyond Türkiye’s borders. As methylene blue migrates from adult anesthesia and cardiac surgery settings, where it is an established rescue for post-bypass vasoplegia, into pediatric septic shock care, the international critical care community faces the same dilemma the Turkish survey has quantified: a cheap, rapidly acting, mechanistically plausible drug is being used on the sickest children in the absence of pediatric randomized controlled trials. Nationwide practice surveys like this one serve as an early warning system, showing where real-world use has drifted ahead of the evidence and identifying the exact questions that future trials must answer, from optimal dosing and timing to mandatory G6PD screening and cardiac assessment. Until those trials arrive, the dye that once stained microbiology slides is staining a new chapter in pediatric critical care, one written largely by clinical instinct rather than by data.

Subject of Research: Clinical use of methylene blue for refractory septic shock in pediatric intensive care

Article Title: Use of methylene blue in the management of refractory shock in pediatric intensive care units: a nationwide assessment of clinical practice in Türkiye

Article References: Ozen, H., Keskin, M. D., Genc, B., & Yilmaz, R. (2026). Use of methylene blue in the management of refractory shock in pediatric intensive care units: a nationwide assessment of clinical practice in Türkiye. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07805-3

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07805-3

Keywords: methylene blue, refractory shock, septic shock, pediatric intensive care, vasoplegic shock, catecholamine resistance, G6PD deficiency, vasoactive-inotropic score, point-of-care ultrasound, nitric oxide pathway, clinical survey, Türkiye

The study, conducted by Özge Sönmez and Ahmet Emre Eşkazan of the Division of Hematology at Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, used a web-based questionnaire to probe how hematologists manage extreme thrombocytosis, the technical term for platelet counts that far exceed the normal range of roughly 150,000 to 450,000 per microliter. Fifty-six hematologists participated in the survey, which was supported by the Turkish Society of Hematology and approved by the local clinical studies ethics committee at Istanbul University-Cerrahpaşa. The authors set out to map real-world clinical behavior in a domain where evidence is thin, expert opinion varies widely, and the consequences of over-treatment or under-treatment can be serious for patients with essential thrombocythemia, one of the classical Philadelphia-negative myeloproliferative neoplasms.

The central finding concerns the platelet threshold at which physicians choose to intensify therapy. Cytoreductive treatment, which uses medications such as hydroxyurea to suppress platelet production in the marrow, was favored by 41.1 percent of respondents once platelet counts reached or exceeded 1000 × 10⁹ per liter, the celebrated million-platelet mark. But when the threshold was raised to 1500 × 10⁹ per liter, the proportion of hematologists opting for cytoreduction jumped to 83.9 percent. In other words, the million mark alone is not a universal trigger for action; it is a point of debate. Only when counts approach one and a half million does a strong majority of specialists converge on drug-based platelet lowering, a pattern that mirrors the cautious, risk-adapted philosophy embedded in contemporary myeloproliferative neoplasm guidelines.

Why does the million mark inspire such hesitation? The answer lies in the biology of extreme thrombocytosis. Very high platelet counts do not simply increase the risk of blood clots; paradoxically, they also raise the risk of bleeding. The mechanism is acquired von Willebrand disease, a condition in which the sheer excess of circulating platelets adsorbs and proteolytically cleaves von Willebrand factor, the adhesive protein that platelets and clotting depend on. As platelets multiply, they effectively devour their own hemostatic infrastructure, and the largest von Willebrand multimers disappear first. A patient with a platelet count of a million or more may therefore present with gastrointestinal bleeding or bruising rather than thrombosis, and giving aspirin to such a patient in the belief that high platelets mean high clot risk can precipitate dangerous hemorrhage.

This biological nuance explains the second pillar of the survey: laboratory assessment. A striking 78.6 percent of hematologists reported testing for von Willebrand factor ristocetin cofactor activity, abbreviated vWF:RCo, at the time of diagnosis of extreme thrombocytosis. This assay measures the functional capacity of von Willebrand factor to support platelet adhesion under shear stress, and it is the workhorse test for detecting the acquired form of the deficiency. The near-universal uptake of this test among survey respondents suggests that the field has internalized the lesson that platelet number alone is an unreliable guide to bleeding risk, and that documenting acquired von Willebrand disease is now considered a standard part of the initial evaluation when counts soar into the extreme range.

Aspirin decisions revealed an equally disciplined logic. In the presence of cardiovascular risk factors and in the absence of acquired von Willebrand disease, 91.1 percent of hematologists favored aspirin therapy for patients with platelet counts of at least 1000 × 10⁹ per liter, and 78.6 percent favored it at counts of at least 1500 × 10⁹ per liter. The slight decline at the higher threshold is telling: the very patients with the most extreme counts are also the most likely to harbor acquired von Willebrand disease, so the antiplatelet drug that protects one patient’s arteries becomes a hemorrhagic hazard for another. The survey thus captures, in numerical form, the delicate balancing act that defines extreme thrombocytosis management, where the same count can argue for and against the same drug depending on a single laboratory result.

When asked why they initiate cytoreductive treatment at all, respondents cited three goals with roughly equal frequency: prevention of thrombosis, prevention of bleeding, and control of symptoms such as headaches, erythromelalgia, and visual disturbances. This even distribution is itself informative. It shows that hematologists do not view cytoreduction solely as an anti-thrombotic strategy. Lowering the platelet count can restore von Willebrand factor levels and relieve bleeding, and it can also ameliorate the microvascular symptoms that plague many patients with essential thrombocythemia regardless of their thrombotic risk score. The therapeutic rationale, in practice, is tripartite, and the survey suggests that experienced clinicians weigh all three aims rather than fixating on any single one.

The most novel element of the report is its comparison with artificial intelligence. The authors posed the same clinical scenarios to AI programs and recorded the recommendations the models produced. The AI-generated advice supported von Willebrand testing, endorsed cytoreductive treatment particularly at platelet counts of 1500 × 10⁹ per liter or above, and generally recommended aspirin only for patients with counts of at least 1000 × 10⁹ per liter who did not have acquired von Willebrand disease. Across several clinical scenarios, the differences between the human specialists and the machine recommendations were few. The authors are careful to frame this comparison as exploratory, and they stop short of claiming that AI can substitute for clinical judgment, but the convergence is noteworthy at a time when large language models are being proposed as clinical decision aids.

The significance of this convergence deserves careful interpretation. On one hand, it suggests that the consensus positions in hematology, such as testing for acquired von Willebrand disease and reserving aggressive cytoreduction for the most extreme counts, are encoded deeply enough in the published literature that AI systems trained on that literature reproduce them faithfully. On the other hand, it raises the question of whether AI is genuinely reasoning or simply echoing the dominant patterns of its training data, including their blind spots. Where expert opinion is divided, as it clearly is at the million-platelet threshold where only about four in ten specialists opt for cytoreduction, an AI that confidently recommends a single course of action could flatten legitimate clinical nuance into false certainty. The survey’s exploratory design is a prudent acknowledgment of that risk.

For patients with essential thrombocythemia, the practical message of the study is reassuring in one respect and cautionary in another. Reassuring, because the management of extreme thrombocytosis appears to follow a coherent, biologically informed playbook: check von Willebrand function, tailor aspirin to its result, and reserve cytoreductive drugs chiefly for the most extreme counts or for patients with thrombosis, bleeding, or disabling symptoms. Cautionary, because the survey also exposes genuine variability at the margins, with more than half of specialists declining to treat at exactly one million platelets while others intervene. As Sönmez and Eşkazan conclude, extreme thrombocytosis itself remains an important driver of treatment decisions, particularly above 1500 × 10⁹ per liter, and the near-agreement between experienced hematologists and AI recommendations offers a provocative glimpse of a future in which algorithms may help standardize care, provided they are validated rigorously and deployed with the same humility that the survey’s authors bring to their own exploratory analysis.

Subject of Research: Clinical management of extreme thrombocytosis in essential thrombocythemia, comparing hematologist survey responses with artificial intelligence recommendations

Article Title: When platelets reach a million: insights from hematologists

Article References: Sönmez, Ö., & Eşkazan, A. E. (2026). When platelets reach a million: insights from hematologists. Annals of Hematology. https://doi.org/10.1007/s00277-026-07183-x

Image Credits: AI Generated

DOI: 10.1007/s00277-026-07183-x

Keywords: essential thrombocythemia, extreme thrombocytosis, platelets, cytoreductive therapy, acquired von Willebrand disease, aspirin, von Willebrand factor, myeloproliferative neoplasms, hematology, artificial intelligence, clinical survey, thrombosis