Epinephrine in Children With Pulmonary Hypertension: A Pilot Study Abstract Objectives: During a pulmonary hypertensive crisis, the marked increase in pulmonary vascular resistance can result in acute right ventricular failure and death. Currently, there are no therapeutic guidelines for managing an acute crisis. This pilot study examined the hemodynamic effects of phenylephrine, arginine vasopressin, and epinephrine in pediatric patients with pulmonary hypertension. Design: In this prospective, open-label, nonrandomized pilot study, we enrolled pediatric patients previously diagnosed with pulmonary hypertensive who were scheduled electively for cardiac catheterization. Primary outcome was a change in the ratio of pulmonary-to-systemic vascular resistance. Baseline hemodynamic data were collected before and after the study drug was administered. Patients: Eleven of 15 participants were women, median age was 9.2 years (range, 1.7-14.9 yr), and median weight was 26.8 kg (range, 8.5-55.2 kg). Baseline mean pulmonary artery pressure was 49 ± 19 mm Hg, and mean indexed pulmonary vascular resistance was 10 ± 5.4 Wood units. Etiology of pulmonary hypertensive varied, and all were on systemic pulmonary hypertensive medications. Interventions: Patients 1-5 received phenylephrine 1 g/kg; patients 6-10 received arginine vasopressin 0.03 U/kg; and patients 11-15 received epinephrine 1 g/kg. μ μ Hemodynamics was measured continuously for up to 10 minutes following study drug administration. Measurements and main results: After study drug administration, the ratio of pulmonary-to-systemic vascular resistance decreased in three of five patients receiving phenylephrine, five of five patients receiving arginine vasopressin, and three of five patients receiving epinephrine. Although all three medications resulted in an increase in aortic pressure, only arginine vasopressin consistently resulted in a decrease in the ratio of systolic pulmonary artery-to-aortic pressure. Conclusions: This prospective pilot study of phenylephrine, arginine vasopressin, and epinephrine in pediatric patients with pulmonary hypertensive showed an increase in aortic pressure with all drugs although only vasopressin resulted in a consistent decrease in the ratio of pulmonary-to-systemic vascular resistance. Studies with more subjects are warranted to define optimal dosing strategies of these medications in an acute pulmonary hypertensive crisis. Stephanie L Siehr, Jeffrey A Feinstein, Weiguang Yang, Lynn F Peng, Michelle T Ogawa, Chandra Ramamoorthy. Pediatr Crit Care Med (2016) PMID: 27144689 Sofie Van Landeghem, ODSC 2023 8
were women, median age was 9.2 years (range, 1.7-14.9 yr), and median weight was 26.8 kg (range, 8.5-55.2 kg). Baseline mean pulmonary artery pressure was 49 ± 19 mm Hg, and mean indexed pulmonary vascular resistance was 10 ± 5.4 Wood units. Etiology of pulmonary hypertensive varied, and all were on systemic pulmonary hypertensive medications. Interventions: Patients 1-5 received phenylephrine 1 g/kg; patients 6-10 received arginine vasopressin 0.03 μ U/kg; and patients 11-15 received epinephrine 1 g/kg. μ Hemodynamics was measured continuously for up to 10 minutes following study drug administration. Measurements and main results: After study drug administration, the ratio of pulmonary-to-systemic vascular resistance decreased in three of five patients receiving phenylephrine, five of five patients receiving arginine vasopressin, and three of five patients receiving epinephrine. Although all three medications resulted in an increase in aortic pressure, only arginine vasopressin consistently resulted in a decrease in the ratio of systolic pulmonary artery-to-aortic pressure. Sofie Van Landeghem, ODSC 2023 9 → The pre-trained English models are not tailored to biomedical texts, so there is no out-of-the-box functionality for patient groups, drugs, etc
{"POS": {"IN": ["SYM", "NUM", "PUNCT"]}, "OP": "+"}, {"LOWER": "received"}, {"POS": {"IN": ["ADJ", "NOUN", "NUM", "ADP", "SYM"]}, "OP": "+"}] matcher.add("TreatmentGroup", [pattern]) matches = matcher(doc, as_spans=True) matches = util.filter_spans(matches) for span in matches: print(span.text) > Patients 1-5 received phenylephrine 1 μg/kg > patients 6-10 received arginine vasopressin 0.03 U/kg > patients 11-15 received epinephrine 1 μg/kg Sofie Van Landeghem, ODSC 2023 → Matcher rules help you explore the data & get a hands-on feel of the complexity of the task → They can help bootstrap annotation through weak labeling https://spacy.io/usage/rule-based-matching 11
supervised model tailored to your domain & business case • In this case, we probably need (at least) ➢ NER & spancat: identify patient groups, drugs, doses, frequencies, outcomes, … ➢ Relation extraction: find the correct relations between patient groups, treatments and outcomes. Sofie Van Landeghem, ODSC 2023 https://spacy.io/usage/training 12
like so: Patient group: <name> Number of patients in the group: <number> Treatment drug or substance: <drug> Treatment dose: <drug> Treatment frequency of administration: <frequency> Treatment duration: <duration> Outcome: <outcome> Patient group: Phenylephrine Group Number of patients in the group: 5 Treatment drug or substance: Phenylephrine Treatment dose: 1 μg/kg Treatment frequency of administration: Single administration Treatment duration: Not specified Outcome: The ratio of pulmonary-to-systemic vascular resistance decreased in three of five patients receiving phenylephrine. Increase in aortic pressure observed. Patient group: Arginine Vasopressin Group Number of patients in the group: 5 Treatment drug or substance: Arginine vasopressin Treatment dose: 0.03 U/kg Treatment frequency of administration: Single administration Treatment duration: Not specified Outcome: The ratio of pulmonary-to-systemic vascular resistance decreased in all five patients receiving arginine vasopressin. Increase in aortic pressure observed. Consistent decrease in the ratio of systolic pulmonary artery-to-aortic pressure observed. Patient group: Epinephrine Group (...) Patients 1-5 received phenylephrine 1 g/kg μ ; patients 6-10 received arginine vasopressin 0.03 U/kg; and patients 11-15 received epinephrine 1 g/kg μ (...) After study drug administration, the ratio of pulmonary-to- systemic vascular resistance decreased in three of five patients receiving phenylephrine, five of five patients receiving arginine vasopressin, and three of five patients receiving epinephrine. Sofie Van Landeghem, ODSC 2023 ChatGPT Input text LLM output 17
structured NLP pipelines • Backends: ➢ External APIs, e.g. OpenAI, Cohere, Anthropic ➢ Open-source models, e.g. Dolly v2, OpenLLaMa, StableLM (via HuggingFace hub) ➢ Connect your favourite model by writing a custom backend! • Tasks: ➢ Define prompt to send to the LLM ➢ Parse the LLM’s response and turn this into structured annotations on spaCy’s Doc objects ➢ Write a custom task definition for your specific use-case! Sofie Van Landeghem, ODSC 2023 https://github.com/explosion/spacy-llm 19
= """ Summarize the trial results in a structured fashion like so: Patient group: <name> Number of patients in the group: <number> Treatment drug or substance: <drug> Treatment dose: <drug> Treatment frequency of administration: <frequency> Treatment duration: <duration> Outcome: <outcome> """ class TrialSummaryTask: def generate_prompts(self, docs: Iterable[Doc]) -> Iterable[str]: for doc in docs: prompt = "Below this instruction, I will provide you with a clinical trial abstract. " prompt += INSTRUCTION + doc.text yield prompt def parse_responses(self, docs: Iterable[Doc], responses: Iterable[str]) -> Iterable[Doc]: ... @registry.llm_tasks("hedgy.TrialSummary.v1") def make_trial_task(): return TrialSummaryTask() 23
like so: Patient group: <name> Number of patients in the group: <number> Treatment drug or substance: <drug> Treatment dose: <drug> Treatment frequency of administration: <frequency> Treatment duration: <duration> Outcome: <outcome> Patient group: Pediatric patients with pulmonary hypertension Number of patients in the group: 15 Treatment drug or substance: Phenylephrine, arginine vasopressin, and epinephrine Treatment dose: Phenylephrine 1 μg/kg, arginine vasopressin 0.03 U/kg, epinephrine 1 μg/kg Treatment frequency of administration: Administered once Treatment duration: Hemodynamic measurements taken continuously for up to 10 minutes following drug administration Outcome: All three medications resulted in an increase in aortic pressure. Only arginine vasopressin consistently resulted in a decrease in the ratio of systolic pulmonary artery-to-aortic pressure. The ratio of pulmonary-to-systemic vascular resistance decreased in three out of five patients receiving phenylephrine, five out of five patients receiving arginine vasopressin, and three out of five patients receiving epinephrine. Studies with more patients are needed to define optimal dosing strategies for these medications in an acute pulmonary hypertensive crisis. Patients 1-5 received phenylephrine 1 g/kg; patients 6-10 received μ arginine vasopressin 0.03 U/kg; and patients 11-15 received epinephrine 1 g/kg μ (...) After study drug administration, the ratio of pulmonary-to-systemic vascular resistance decreased in three of five patients receiving phenylephrine, five of five patients receiving arginine vasopressin, and three of five patients receiving epinephrine. Although all three medications resulted in an increase in aortic pressure, only arginine vasopressin consistently resulted in a decrease in the ratio of systolic pulmonary artery-to-aortic pressure. Sofie Van Landeghem, ODSC 2023 GPT 3.5 [components.llm.task] @llm_tasks = "hedgy.TrialSummary.v1" Input text LLM output 24
fashion like so: Patient group: <name> Number of patients in the group: <number> Treatment drug or substance: <drug> Treatment dose: <drug> Treatment frequency of administration: <frequency> Treatment duration: <duration> Outcome: <outcome> Patient group: Phenylephrine Group Number of patients in the group: 5 Treatment drug or substance: Phenylephrine Treatment dose: 1 μg/kg Treatment frequency of administration: Single administration Treatment duration: Not specified Outcome: The ratio of pulmonary-to-systemic vascular resistance decreased in three of five patients receiving phenylephrine. Increase in aortic pressure observed. Patient group: Arginine Vasopressin Group Number of patients in the group: 5 Treatment drug or substance: Arginine vasopressin Treatment dose: 0.03 U/kg Treatment frequency of administration: Single administration Treatment duration: Not specified Outcome: The ratio of pulmonary-to-systemic vascular resistance decreased in all five patients receiving arginine vasopressin. Increase in aortic pressure observed. Consistent decrease in the ratio of systolic pulmonary artery-to-aortic pressure observed. Patient group: Epinephrine Group (...) Patients 1-5 received phenylephrine 1 g/kg μ ; patients 6-10 received arginine vasopressin 0.03 U/kg; and patients 11-15 received epinephrine 1 g/kg μ (...) After study drug administration, the ratio of pulmonary-to- systemic vascular resistance decreased in three of five patients receiving phenylephrine, five of five patients receiving arginine vasopressin, and three of five patients receiving epinephrine. Sofie Van Landeghem, ODSC 2023 ChatGPT Input text LLM output 25
First, identify all patient groups with distinct treatments. Then, for each patient group, write down the following: Patient group: <name> Number of patients in the group: <number> Treatment drug or substance: <drug> Treatment dose: <drug> Treatment frequency of administration: <frequency> Treatment duration: <duration> Outcome: <outcome> Sofie Van Landeghem, ODSC 2023 GPT 3.5 [components.llm.task] @llm_tasks = "hedgy.TrialSummary.v2" Patient group: Phenylephrine group Number of patients in the group: 5 Treatment drug or substance: Phenylephrine Treatment dose: 1 μg/kg Treatment frequency of administration: One-time administration Treatment duration: Not specified Outcome: Ratio of pulmonary-to-systemic vascular resistance decreased in three out of five patients after study drug administration Patient group: Arginine vasopressin group Number of patients in the group: 5 Treatment drug or substance: Arginine vasopressin Treatment dose: 0.03 U/kg Treatment frequency of administration: One-time administration Treatment duration: Not specified Outcome: Ratio of pulmonary-to-systemic vascular resistance decreased in all five patients after study drug administration. Consistent decrease in the ratio of systolic pulmonary artery-to-aortic pressure noted. Patient group: Epinephrine group (...) Patients 1-5 received phenylephrine 1 g/kg μ ; patients 6-10 received arginine vasopressin 0.03 U/kg; and patients 11-15 received epinephrine 1 g/kg μ (...) After study drug administration, the ratio of pulmonary-to- systemic vascular resistance decreased in three of five patients receiving phenylephrine, five of five patients receiving arginine vasopressin, and three of five patients receiving epinephrine. LLM output Input text 26
def parse_responses(self, docs: Iterable[Doc], responses: Iterable[str]) -> Iterable[Doc]: for doc, response in zip(docs, responses): patient_groups = [] ... while ... patient_group = response[start_index:end_index].strip() patient_groups.append(patient_group) ... matcher.add("Patient_Group", [nlp.make_doc(text) for text in patient_groups]) ... matches = matcher(doc, as_spans=True) doc.ents = spacy.util.filter_spans(matches) yield doc 27 → Downstream processes can now use the LLM output in a structured way via the Doc object
in the group: 5 Treatment drug or substance: Phenylephrine 1 μg/kg Treatment dose: As mentioned above Sofie Van Landeghem, ODSC 2023 Number of patients in the group: 15 Treatment drug or substance: Group 1: Patient 1-5 received phenylephrine 1 μg/kg Group 2: Patient 6-10 received arginine vasopressin 0.03 U/kg Group 3: Patient 11-15 received epinephrine 1 μg/kg Treatment frequency of administration “Administered once” “Single administration” “One-time dose” “One time” “Single dose” “One-time administration” “once” openai.error.RateLimitError 30
zero-shot predictions https://prodigy.ai/features/large-language-models Manual curation Evaluation data - Measure pipeline performance Training data - Train a supervised model 35 Examples for few-shot learning - Tune the LLM
TextCat NER ➢ Only send texts/sentences with certain topics/entities to the LLM ➢ Avoid inducing unncessary costs ➢ Adjust prompt according to earlier classification and/or identified entities ➢ ... LLM 37
LLM Entity linking ➢ Normalize the (free-text) LLM responses ➢ Connect to a knowledge base (e.g. through entity linking) ➢ Make the (unpredictable) LLM responses more robust for ingestion by downstream processes ➢ ... 38 Rules
from text and makes it available to down-stream business applications in a structured form • Large Language Models have impressive text generation/understanding abilities • It’s become super easy to prototype NLP applications with LLMs • When building a production-ready pipeline, you need to consider other traits such as customizability, robustness, inference cost, network latency, etc. • spaCy is a production-ready NLP framework written for developers • Its latest extension spacy-llm allows easy integration of LLMs into structured NLP pipelines • LLM-assisted annotation allows fast bootstrapping of training/evaluation data 39
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