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Literature review
Introduction
According to The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) sepsis is “a syndrome of physiologic, pathologic, and biochemical abnormalities induced by infection” (Singer et al. 2016) and the reported incidence is increasing. The Surviving Sepsis Campaign has given a variety of recommendations, including the use of norepinephrine (Evans et al. 2021). In the guidelines and the rationale behind it, there is a lack of recommendations on the timing of the use of norepinephrine. In this literature review, the author wishes to investigate if there are benefits in patient-oriented outcomes in the use of early norepinephrine and thereby also the use of norepinephrine in the prehospital settings.
Basic physiology and connection in sepsis and norepinephrine
Sepsis can lead to a vasodilatory state and cause dysfunction of the vascular endothelium and loss of barrier integrity (Angus and Van der Poll 2013). Norepinephrine serves as a vasoconstrictor and can stabilize and reduce endothelial permeability (Joffre et al. 2021).
Material and methods
All articles included in this analysis were retrieved as described in the MS planner assignment. A simple overview can be seen in Appendix 1. All articles have been critically appraised using CASP tools as shown in Appendix 2-8.
Norepinephrine and fluids
Fluid resuscitation in sepsis might play a role but comes with the risk of fluid overload leading to potentially harmful events such as tissue and lung edema and organ dysfunction. (O’Connor and Prowle 2015). Can the introduction of norepinephrine (NE) in the early management of sepsis reduce the amount of fluid administrated to adults with sepsis? According to Akbar and colleagues that might be the case. In a randomized control trial, they showed that when NE is introduced with fluid administration, the amount of fluid administrated within the first 24 hours, decreased significantly (Akbar et al. 2021). The study used a comparison of urinary albumin-to-creatinine ratio, serum creatinine, arterial oxygen partial pressure-fractional inspired oxygen ratio, and intra-abdominal pressure as indicators of the risk of fluid overload. All indicators were in favour of the group that received NE as part of the initial treatment. In addition, the study showed a significant reduction in the total amount of fluid administrated to patients receiving NE as part of the initial treatment. Indicating that the use of NE can reduce the amount of fluid administrated to patients in the resuscitation of sepsis. This could have an impact on patient-oriented outcomes, the question is which outcomes? And does timing matter?
Norepinephrine in a timely manner
Alshahrani et al try to shed some light on that. In a retrospective analysis of data collected in the ICU, they found that in patients with sepsis, the time to first dose of NE was associated with higher survival rates.
It was revealed that 3–3.99 hours was the highest mortality rates (50%), followed by 2–2.99 (42.9%) and 4 hours or more (40%). On the other hand, highest survival rates have been detected on 0–0.99 (68.8%) and 1–1.99 (68.6%).
(Alshahrani and Alatigue 2021)
In this study, data is not transparent enough to tell if NE was the primary reason for better outcomes. Groups are only comparative in terms of outcome and not intervention. Therefore, the group with a worse outcome also could represent the sickest. That transparency is present in a study by Bai et al that showed a significant decrease in 28-day mortality in patients with septic shock when NE was administered within 2 hours of onset (Bai et al. 2014). This study reported similar baseline characteristics between patient groups in septic shock, that either received NE before or after 2 hours. A higher baseline serum lactate was reported in the early group, which eventually had better outcomes in terms of survival, total amount of NE administrated, and duration of hypotension. This study also reported similar Acute Physiology and Chronic Health Evaluation (APACHE II(Knaus et al. 1985)) scores in the two intervention groups. Results reported by Bai et al. showed a tendency towards the use of early administrated norepinephrine but also had some weaknesses in study design since this was a retrospective study. Prospective collection of data and randomization were done by Ebied et al. who randomized 64 patients with severe sepsis into two treatment regimes. One group was resuscitated with only ringer lactate, 30 ml/kg, and if fluid resuscitation was inadequate NE was introduced. The other group received NE along with fluid resuscitation with ringer lactate 30 ml/kg. The group with early administrated NE did better in terms of time to adequate MAP of 65 mmHg, which was the primary outcome. The same group also received a smaller total amount of both fluids and NE, had shorter ICU stays and a decreased 30-day mortality (Ebied et al. 2023). The study had a small sample size, which made it possible to declare a significant decrease in mortality when the absolute difference in non-survivors was only 5 patients. And like all other studies previously mentioned, this was a study conducted inhospitally. One included study looked at prehospital norepinephrine administration, with 30-day mortality and length of ICU stay as primary outcomes. Jouffroy et al. made a retrospective analysis of data collected from a prehospital mobile intensive care unit, that is dispatched to the sickest prehospital patients. They found a decrease in both outcomes when NE was administrated prehospital. Since the treatment groups were not randomized, some baseline characteristics differed. The early NE group was reported to have higher prehospital blood lactate, lower MAP, and lower GCS and also received a higher amount of fluids (ml/kg). Indicating that the group receiving NE prehospital represents the sickest group. The authors reported that “Multivariate logistic regression of IPTW retrieved a significant decrease of 30-day mortality among the prehospital norepinephrine group” (Jouffroy et al. 2022). They used a propensity score to adjust for expected outcomes and could report a difference in mortality and length of stay. Jouffroy and colleagues did not report any adverse events for any of the groups, leaving the question about the safety of early administration of NE open.
Is it safe and is it for all?
A study, by Messina et al., did investigate the safety of NE administration outside of ICU settings. In this retrospective safety report, they investigated the prevalence of adverse events due to peripheral administrated NE in the emergency department (ED). They also considered the effect on outcomes in patients with a ceiling of care limited to care in the ED compared to those admitted to an ICU. In terms of outcomes, admission to the ICU was the only independent factor considered significantly associated with in-hospital-mortality (Messina et al. 2021) The time for initial NE infusion varied too much in the two comparison groups to tell anything about the interventions’ effect on outcomes such as mortality. However, the study perhaps can tell us something about the safety of administrating NE. Patients in this study all received NE. When NE was initiated in the ED, it was administrated in peripheral vascular access and infused with an electronic infusion pump, limiting the risk of paravenous infusion and unintended boluses. Of the 127 patients included in this study, only 1 had a confirmed extravasation. The ED where the study was conducted is not comparable to the prehospital setting, but in the matter of patient-to-caregiver ratio, prehospital settings could be better since only one patient is transported at a time, making it reasonable to think that in prehospital settings where infusion pumps and contentious monitoring of the patient is possible, it could be safe to administrate NE. Other side effects such as cardiovascular events and allergic reactions were not reported. This, and other studies, included data about the site of infection. However, the data was not used to analyse if NE was beneficial in all patients in terms of the origin of infection. A study by Shi et al. looked at the early use of vasopressors in patients with acute pancreatitis and found that early use of vasopressors was associated with an increase in mortality (Shi et al. 2023). When data from the study were further analysed it was shown that this was true in some vasopressors but not all. There was no significant association between the use of NE and mortality. Nevertheless, it could indicate that the origin of infection should be considered when treating with vasopressors, including NE.
Discussion
Data included in this review demonstrates that early administration of NE in sepsis patients is beneficial. These findings are consistent with the findings of Xu et al. that showed that initiation of NE within 3 hours of sepsis recognition is associated with 28-day survival (Xu et al. 2022). An RCT by Permpikul et al. concluded a correlation between early NE and 6-hour sepsis control (Permpikul et al. 2019). Furthermore, a systematic review and meta-analysis of 5 RCTs had similar findings and conclusions (Li et al. 2020). Nevertheless, most of the data is collected retrospectively, with the risk of documentation bias (Norvell 2010) and the few RCTs have small sample sizes and are single-centred studies. Often the sickest patients are excluded and there is also a great risk of publication bias since most studies are positive and in favour of intervention. It is also important to notice that this review is done by a single researcher with limited time and experience. Which is why relevant literature could have been unintentionally overlooked. The use of early NE should be investigated further and larger high-quality RCTs are needed.
Conclusion
There is a tendency towards the use of early norepinephrine in patients with sepsis. It is safe and has an impact on mortality, fluid overload and length of stay in the ICU. While the early use of NE has a positive effect on patient-oriented outcomes, it is worth considering the modality and origin of the infection. In setups where NE can be safely administrated current data indicates that early use of it is beneficial in patients with sepsis.
References
Akbar, R., George, Y., Madjid, A.S., Sedono, R. and Tantri, A. (2021) ‘Early administration of norepinephrine prevents the occurrence of fluid overload in the resuscitation of septic shock patients’, Critical Care and Shock, September 2021, 257-268.
Alshahrani, M.S. and Alatigue, R. (2021) ‘Association between early administration of norepinephrine in septic shock and survival’, Open Access Emergency Medicine, 13, 143-150, available: http://dx.doi.org/10.2147/OAEM.S298315.
Angus, D.C. and Van der Poll, T. (2013) ‘Severe sepsis and septic shock’, New England journal of medicine, 369(9), 840-851.
Bai, X., Yu, W., Ji, W., Lin, Z., Tan, S., Duan, K., Dong, Y., Xu, L. and Li, N. (2014) ‘Early versus delayed administration of norepinephrine in patients with septic shock’, Critical Care, 18(5), available: http://dx.doi.org/10.1186/s13054-014-0532-y.
Ebied, G.O.M., EL-Baradey, G.F., Sayed, N., El-Shmaa, M. and Mostafa, T.A.-H. (2023) ‘The impact of early norepinephrine administration on outcomes of patients with sepsis induced hypotension, randomized controlled prospective study’, IJMA, 6(2), 90-96.
Evans, L., Rhodes, A., Alhazzani, W., Antonelli, M., Coopersmith, C.M., French, C., Machado, F.R., Mcintyre, L., Ostermann, M. and Prescott, H.C. (2021) ‘Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021’, Critical care medicine, 49(11), e1063-e1143.
Joffre, J., Lloyd, E., Wong, E., Chung-Yeh, C., Nguyen, N., Xu, F., Legrand, M. and Hellman, J. (2021) ‘Catecholaminergic vasopressors reduce toll-like receptor agonist-induced microvascular endothelial cell permeability but not cytokine production’, Critical care medicine, 49(3), e315-e326.
Jouffroy, R., Hajjar, A., Gilbert, B., Tourtier, J.P., Bloch-Laine, E., Ecollan, P., Boularan, J., Bounes, V., Vivien, B. and Gueye, P.-N. (2022) ‘Prehospital norepinephrine administration reduces 30-day mortality among septic shock patients’, BMC Infectious Diseases, 22(1), 1-10.
Knaus, W.A., Draper, E.A., Wagner, D.P. and Zimmerman, J.E. (1985) ‘APACHE II: a severity of disease classification system’, Critical care medicine, 13(10), 818-829.
Li, Y., Li, H. and Zhang, D. (2020) ‘Timing of norepinephrine initiation in patients with septic shock: a systematic review and meta-analysis’, Critical Care, 24, 1-9.
Messina, A., Milani, A., Morenghi, E., Costantini, E., Brusa, S., Negri, K., Alberio, D., Leoncini, O., Paiardi, S., Voza, A. and Cecconi, M. (2021) ‘Norepinephrine infusion in the emergency department in septic shock patients: A retrospective 2-years safety report and outcome analysis’, International Journal of Environmental Research and Public Health, 18(2), 1-9, available: http://dx.doi.org/10.3390/ijerph18020824.
Norvell, D.C. (2010) ‘Study types and bias—Don’t judge a study by the abstract’s conclusion alone’, Evidence-based spine-care journal, 1(02), 7-10.
O’Connor, M.E. and Prowle, J.R. (2015) ‘Fluid overload’, Critical care clinics, 31(4), 803-821.
Permpikul, C., Tongyoo, S., Viarasilpa, T., Trainarongsakul, T., Chakorn, T. and Udompanturak, S. (2019) ‘Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial’, American journal of respiratory and critical care medicine, 199(9), 1097-1105.
Shi, H., Sun, S.Y., He, Y.S. and Peng, Q. (2023) ‘Association between early vasopressor administration and in-hospital mortality in critically ill patients with acute pancreatitis: A cohort study from the MIMIC-IV database’, European Review for Medical and Pharmacological Sciences, 27(2), 787-798, available: http://dx.doi.org/10.26355/eurrev_202301_31080.
Singer, M., Deutschman, C.S., Seymour, C.W., Shankar-Hari, M., Annane, D., Bauer, M., Bellomo, R., Bernard, G.R., Chiche, J.-D. and Coopersmith, C.M. (2016) ‘The third international consensus definitions for sepsis and septic shock (Sepsis-3)’, Jama, 315(8), 801-810.
Xu, F., Zhong, R., Shi, S., Zeng, Y. and Tang, Z. (2022) ‘Early initiation of norepinephrine in patients with septic shock: A propensity score-based analysis’, The American Journal of Emergency Medicine, 54, 287-296.
