Norepinephrine Challenges – Brittany Bissel Turpin

The session discusses the current challenges with norepinephrine, concentration, variability, and the research priorities of the surviving sepsis campaign.

The session elaborates on the reported norepinephrine concentrations and takes these considerations into practice at a multicentre and multinational level. A task force was developed based on recognition and awareness of a group of different individuals. It included many clinicians who started to develop or become aware of potentially inconsistent reports of norepinephrine and how we report norepinephrine concentrations in our literature. Norepinephrine is available as a salt formulation. Salt formulations are necessary for about 50% medicinal agents and 70% of intravenous agents, to administer these medications safely to patients. Norepinephrine salt formulation or the conjugated salt form allows it to be administered intravenously due to its underlying low water solubility. However, there is little attention given to salt formulations and there are implications in reporting. The 3 salt formulations used with nor-epinephrine are norepinephrine bitartrate, norepinephrine tartrate, and norepinephrine hydrochloride. The salt formulation is heavier than just the active pharmaceutical ingredient. There is not a huge impact in which salt formulation is used with a slightly different isomer with water molecules. The salt formulation or base concentration reported in the labelling is based on the manufacturer and the country. About half of intensivists are unaware of the salt formulation that is given in their intensive care unit or their critical care unit. In the USA, norepinephrine exposure is discussed based on the API or the base concentration. A review of the formulation used in 32 countries found that prescribing information consistently does include salt formulation and the base concentration. However, there lies a difference in the reporting of the active drug label, with 4 countries listing the salt formulation as the concentration on the label. Improperly reporting the salt concentrations has certain implications. The implications for research in multinational multicentre studies when using different standards for dose reporting can have inconsistency in findings and protocol. The other implications include confusion in thresholds for adjunctive treatment initiation, heterogeneity in clinical practice, and inappropriate use of severity or clinical assessment scoring tools. Concerning clinical trials, there may be implications associated with inclusion, timing, or parameters for patients based on their centre or country depending on how fast or slow the titration is. Some clinical trials have redefined enrolment thresholds for norepinephrine exposure or norepinephrine equivalence. While considering the dose reported by the salt formulation versus the base concentration, there is potential for very different predictions in mortality considering the concentration used for calculation. Its relevance to clinical practice is seen through the organ failure assessment scores, surviving sepsis guidelines, extracorporeal life support guidelines, and vasopressor conversion calculations. Norepinephrine equivalency is utilized in comparing different agents, comparison of different settings, and in eligibility criteria and outcomes in clinical trials. Concerning clinical approaches at the bedside, dose reporting helps to consider weaning agents based on dose reporting and the initiation of adjuncts.

In conclusion, there are a few different options for salt forms of norepinephrine; the utilization and dose reporting vary by manufacturer or country. It can impact several domains such as drug operations, clinical bedside practice, or research. It is recommended to have a global adoption of a uniform standard for norepinephrine reporting and formulations.

Contemporary Research Priorities – Prof. Sheila Nainan Myatra

The session discussed the publication on surviving sepsis campaign research priorities. The Surviving Sepsis Research Committee is a multi-professional group that has representation from the European Society of Intensive Care Medicine and the Society of Critical Care Medicine. The committee was chosen by the Presidents of both organizations who decided to include authors with a wide variety of topics related to sepsis. Each member was asked to submit 5 research questions on any subject that they felt would improve the understanding of sepsis. Then, the task force explicitly told them to pick the topics that they felt were most important. Which was not restricted to any particular area or not restricted to what was already covered or not covered by the previous guidelines. The expectation was that this open-ended process would lead to research questions spanning a broad spectrum, especially unanswered essential sepsis-related questions. There were 5 top clinical priorities questions and 5 top basic science priorities questions. The research priorities questions focused on what is known about the topic, the gaps in knowledge, including a critique of whatever evidence exists about this, and future directions in which the research should progress. and were listed in the order of patient management. The presenter elaborated on a few of the clinical questions. The first question was “What is the best strategy for screening and identification of patients with sepsis? Can predictive modelling be used in real-time to assist recognition of sepsis?” What is known about this is that the 2021 Surviving Sepsis guidelines recommended that healthcare systems should have performance improvement programs for sepsis, including screening. Identification is crucial since any delay in treatment is associated with outcomes; it requires the recognition of infection, acute organ dysfunction, and domination, and also that this is due to a dysregulated host response. It is important to his kind of clinical deterioration and poor outcomes. The real gaps in the knowledge are the best screening tool for sepsis. It is difficult to create these tools without the standards for diagnosing infections, sepsis-dysregulated host response, or organ dysfunction. Despite the interest and growth in automated sepsis screening models, there is a lack of high-quality evidence of the benefit of routine care. In the future, there is a need for studies to determine whether these various sepsis algorithms that are generalizable to different electronic health records have accurate sensitivity, specificity, and also positive predictive value to be incorporated into the clinical workflow. There are studies needed to test if automated sepsis algorithms improve outcomes compared to routine care. These studies should not only be large-scale observation studies but also prospective randomized controlled trials to add value to the algorithm. Based on this, the various questions that need to be looked at are- What defines a dysregulated host response? How should sepsis algorithms be trained and what should be used as a gold standard? How is automated sepsis screening best implemented into clinical workflow? When implemented well, can automated sepsis screening algorithms improve care processes and also outcomes as compared to the usual care? How is sepsis screening best implemented in low-resource settings? The second question was what causes organ injury and dysregulated dysfunction in sepsis? How should it be defined and how can it be detected? The third question was “How should fluid resuscitation be individualized-initially and beyond?” It further had subsets that elaborated on the optimal fluid management in the first 24 hours, the best hemodynamic tool to predict fluid responsiveness, and the best fluid for initial resuscitation of sepsis-induced hypoperfusion. The fourth question was “What was the best vasopressor approach for treating the different phases of septic shock?”. The subset of questions included when should one initiate vasopressors. Can adrenaline be used? In patients with septic shock receiving norepinephrine and vasopressin, which drug should be weaned off first? The fifth question was “Can a personalized/precision medicine approach identify optimal therapies for improving patient outcomes?” There has been significant progress for each of the questions. However, 4 of the current top 5 clinical priorities in the new surviving sepsis guidelines are from the previous iteration of the 2018 guidelines. Although the few basic research questions have translated into improved outcomes, the majority of the basic science priorities have changed since 2018. The general limitation of the research priorities is that it is an inherently subjective process. The panel was composed of intensivists who may not have managed sepsis. Some countries had higher representation but Africa was not represented. Additionally, there is significantly less knowledge about sepsis management in resource-limited settings and needs to be incorporated in future iterations. For some elements of the research to reach the patient, there are pragmatic elements to its success that need to be considered including explicitly linking the research performance to implementation science.

In conclusion, surviving sepsis research priorities are designed to be a catalyst for the research required in sepsis. The knowledge advances with various iterations of the surviving sepsis campaign guideline have allowed evidence-based recommendations for management. However, there are research gaps and once they are addressed will yield very strong recommendations.

Society of Critical Care Medicine’s Critical Care Congress (SCCM 2024), Phoenix, Arizona, USA, Jan 21-23, 2024