Noradrenaline Utilisation and Hemodynamic Trends in Critically Ill Patients: An Observational Study from a Tertiary Care Hospital

Abstract

Background: Noradrenaline is a high-risk medication used to regulate blood pressure as a vasopressor. The dosing strategy plays a crucial role in managing blood pressure, MAP, and heart rate, but needs close monitoring to reduce some of its adverse events in critical care. Materials and methods: Patients admitted to the ICU, HICU, or CCU diagnosed with shock and treated with noradrenaline were included in this study. Three-time points were selected: T1 (the first hour of norepinephrine infusion), T24 (the 24 hours that followed T1), and T peak (the maximal dose taken during the first 24 hours of treatment). The Blood pressure, heart rate, MAP, and dose were assessed based on these three time points to determine the impact of noradrenaline. Several laboratory parameters were considered before and after noradrenaline. Results: A total of 70 patients were included in the study, most of whom were male, primarily aged between middle and old. Septic shock was the most common indication for noradrenaline. The maximum number of days Norad used was 12. However, in a higher number of patients, it was used for 3 days. Noradrenaline significantly increased systolic blood pressure from 87.73 ± 17.06 mmHg at baseline (T0) to 108.36 ± 21.34 mmHg at 1 hour (T1), remaining stable at 107.55 ± 22.96 mmHg (T24) and rising to 115.39 ± 24.51 mmHg post-discontinuation. Similarly, the DBP increased from 53.84 ± 12.85 mmHg at T0 to 66.18 ± 12.85 mmHg at T1 and a slight decrease at 24 hours. Although there was a decline in heart rate at 102 from baseline to 87 bpm after treatment. A total of 59 drug interactions were found with various drugs, most of which were seen with furosemide. Conclusion: In this study of 70 patients under noradrenaline therapy, varied patterns of outcomes and results were noted. 34% were transferred to the ward, and 30% were also successfully discharged. The mortality rate of 25.1% shows that there is room for improvement in the treatment regimen. Although the dosing strategy in managing BP, MAP and HR were seen to be effective, there is room for development.

Keywords

Introduction

Shock is a critical condition that arises when the body fails to receive adequate blood circulation, which results in a lack of oxygen and nutrients for cells and organs, hindering their proper function. Immediate medical attention is essential for shock, as it can quickly deteriorate. Up to 20% of individuals experiencing shock may succumb to the condition.¹Shock can be septic, cardiogenic, hypovolemic, anaphylactic, or associated with burns, trauma and haemorrhage. It poses challenges in one-third of intensive care units.² Noradrenaline, also known as norepinephrine, is an inotrope and a vasopressor that induces vasoconstriction. It is an endogenous catecholamine that occurs naturally and is a sympathomimetic. Noradrenaline is a reasonable first-line treatment when blood pressure needs to be restored.^3,4 It primarily raises blood pressure and causes peripheral vasoconstriction by stimulating the alpha 1 receptor. At larger doses, it also exhibits modest beta 1 receptor agonist action, which has a favourable inotropic impact on the heart.⁵It exhibits minimal to no beta 2 or alpha 2 activity and is essentially agnostic at alpha 1 and beta 1 receptors. The beta 1 action may be more prominent and increase cardiac output at low dosages (less than 2 mcg/min). On the other hand, the alpha 1 effect can be more prominent at doses of more than 3 mcg/min. Vasoconstriction will arise from the enhanced activation of alpha 1 receptor, and a dose-dependent intravenous solution containing 1 mg/ml, 4 mg/250 ml in dextrose 5%, and 8 mg/250 ml in dextrose 5% is available. Since noradrenaline has a half-life of only 2.5 minutes, it is usually administered via continuous infusion.^5,6

However, the norepinephrine dose itself is a clinically meaningful metric with a number of important considerations. Specifically, knowing the global variations in norepinephrine reporting as a base or salt formulation changes the meaning of different doses of norepinephrine and clinical dose responses compared across hospitals and countries. ⁶ Studying noradrenaline in critically ill patients is crucial because it's often used as a medication to support blood pressure in these individuals. Understanding its effects, optimal dosing, and potential side effects can help improve patient outcomes and guide treatment decisions in intensive care settings. Additionally, dysregulation of noradrenaline levels can occur in critical illness, contributing to complications such as septic shock. Therefore, research in this area can provide insights into the pathophysiology of critical illness and inform therapeutic strategies.^2,3,5

MATERIALS AND METHODS:

Study population:

A total of 70 patients were included in the study. The study population included patients who were 18 years and above, diagnosed with either septic shock, cardiogenic shock or hypovolemic shock, admitted to the critical care unit, who were receiving Noradrenaline therapy.

Study design:

A prospective observational study was conducted in the department of critical care units at a tertiary care hospital from March 2024 to August 2024. After obtaining verbal consent from the patient or their legal representative, Baseline data included demographic details such as age, sex, weight, start date of drug administration, date of discontinuation, hemodynamic parameters (BP, MAP, heart rate) and survival status (discharged or deceased), as well as other laboratory data, was collected and documented in a suitably designed case report form. The hemodynamic parameters were recorded at predefined time periods, i.e. at baseline(T0), T1(first hour of infusion), T24(after 24 hours of infusion), Tpeak(Maximum dose conc.) and after discontinuation (Tafter). The required follow-ups were also documented up to discontinuation of drugs. The dose of noradrenaline in mcg/kg/min was calculated from nursing monitoring charts using the following formula.      

mcg/kg/min =  

Rate(ml/hr) x amount in flask

Total volume(ml) x weight x Time in min

The required dilution strength and infusion rates were recorded from the medication charts. Concomitant drugs along with the study drug were assessed for possible drug-drug interaction using apps like Micromedex®, Lexicomp® and Medscape®. Clinical and demographic data were compiled using descriptive statistics. Categorical variables were expressed as frequencies and percentages, whereas continuous variables were expressed as mean ± standard deviation.

RESULTS:

The study population consisted of 70 patients, categorised into two age groups. Most (54.3%, n=38) of patients fell within the 18-59 age range, while 45.7% (n=32) were 60 years or older. Significantly more middle-aged people were on noradrenaline support. The trend suggests a higher number of middle-aged patients required noradrenaline support. The overall patient distribution by gender showed that 60% were male and 40% female. A higher proportion of males were receiving noradrenaline in the critical care setting.

Table 1: Diagnostic characteristics of the study population.

Diagnostic characteristics:
Duration of Noradrenaline use (No. of days)	No. of patients		Death n (%)
3	18	25.71	3(16.67)
2	17	24.29	0
1	10	14.29	1(5.56)
5	10	14.29	5(27.78)
4	8	11.43	4(22.22)
6	5	7.14	0
9	1	1.43	0
12	1	1.43	0
Indications of Noradrenaline
Septic shock	44	62.90	-
Cardiogenic shock	5	7.10	-
Hypovolemic shock	4	5.70	-
Septic/ hypovolemic shock	8	11.40	-
Septic/ cardiogenic shock	4	5.70	-
Others	5	7.10	-

The accompanying Table 1.A illustrates the duration of noradrenaline use and mortality rates among critically ill patients. Three days was the most typical duration of noradrenaline support, followed by two days. While some patients received noradrenaline support for up to 12 days, the shortest duration recorded was 1 day. The overall indications of noradrenaline use were most dominant in septic shock, with a massive percentage of 62.90%, followed by cardiogenic shock, hypovolemic shock, septic/hypovolemic shock, septic/ cardiogenic shock, and other kinds of shock namely neurogenic shock and haemorrhagic shock. Noradrenaline increased MAP significantly from the baseline (T0) to after 1 hour (T1) and slightly decreased at 24 hours (T24) of the drug use, indicating some stabilisation (Table 2A). After discontinuation of noradrenaline (T After), MAP further increased, which shows the impact was there even after the discontinuation of the drug.    

Figure 1.A: Scattered plot showing the impact of noradrenaline on mean arterial pressure

Figure 1.B: Scattered plot showing the impact of noradrenaline on heart rate

The trend suggests that Noradrenaline increased heart rate from pre-noradrenaline (T0) to after 1 hour (T1), and then it declined through T24 and post-administration (Table 2B). Since noradrenaline concentration mostly peaks at T1 and is tapered following the T1 period according to the MAP, which explains the decline in heart rate. Although Noradrenaline administration leads to a progressive increase in heart rate, with a gradual decline in noradrenaline concentration, the heart rate concurrently declined following the T1 period. The most significant decrease occurs after 24 hours.

Systolic and diastolic blood pressures were seen to be increased significantly within the (T1) first hour of noradrenaline initiation. They remained stable over the next 24 hours(T24), in line with the improvement seen in mean arterial pressure. The parallel changes in SBP, DBP, and MAP suggest a sustained increase in vascular tone rather than a short-lived pressor effect. This indicates that noradrenaline effectively improved overall vascular support, leading to stable perfusion pressures without marked fluctuations in individual blood pressure components.

Table 2: Relationship Between Noradrenaline Dose, Mean Arterial Pressure, and Heart Rate at various time points.

Time period	Average Noradrenaline Dose (µg/kg/min)	Average MAP (mmHg)	Average Heart Rate (bpm)
T1	0.43	78.62	100.6
T24	0.23	76.55	91.6
T Peak	0.47	77.24	96.68
T After	0.04	84.76	87.1

The average noradrenaline dose used across the four time periods generally ranged from 0.04 to 0.47 µg/kg/min (Table 2). In most patients, the initial dose (T1) and the peak dose (T peak) were the same, as noradrenaline was usually started at a higher dose and then adjusted gradually. The dose was titrated to achieve a target MAP of more than 65 mmHg and was subsequently tapered over time. Once adequate MAP was maintained, noradrenaline was gradually reduced and eventually discontinued. It was found that noradrenaline was preferably diluted in normal saline and mainly administered through a central venous line, as central access delivers the drug close to the heart, allowing rapid dilution and spread into the circulation. This helps reduce local tissue injury and allows safer, more reliable infusion of the drug.

The table 3 shows changes in some selective lab parameters and significant improvement after noradrenaline therapy. A declining change in the leukocyte counts was observed, and also a decline in creatinine levels, which suggests improved renal function. Tissue perfusion and metabolic status were seen following the reduction of serum lactate, and increased pH function and bicarbonate values. These laboratory improvements occurred alongside overall clinical stabilisation and cannot be attributed solely to noradrenaline therapy.

Among the 70 patients included in the study, we found 59 potential drug-drug interactions with Noradrenaline which were evaluated using the Lexicomp app. The most frequent interactions were with drugs like diuretics (furosemide, Torsemide) – 26 interactions, followed by beta blockers, namely Bisoprolol and Carvedilol and Sedatives including Midazolam.

Following the initiation of noradrenaline therapy, the therapeutic outcome showed significant improvement where 24 patients were stabilised and shifted to the ward and 21 patients were successfully discharged. Despite the positive impact of noradrenaline therapy, mortality remained considerable, with 18 patients (25.1%) who died, which reflects the severity and seriousness of patients requiring vasopressor. The remaining 7 patient left against medical advice, which doesn’t really affect the clinical outcomes of the therapy. Although the clinical outcomes observed in this study cannot be attributed solely to noradrenaline therapy, underlying disease severity and the use of concurrent treatments and other such factors are likely to have contributed to patient outcomes.

DISCUSSION

Noradrenaline is a potent vasopressor and an inotrope that causes vasoconstriction. It is considered a first-line treatment during a hypotension crisis, particularly in shock, which may explain the wide range of usage in the present study. The study included 70 patients on noradrenaline therapy, where the gender distribution showed 60% of males as the majority treated with noradrenaline and 40% of females as the minority gender. The greater proportion of male patients most likely reflects ICU admission trends rather than gender-specific differences in vasopressor responsiveness. In comparison, a similar study conducted by Sapkota K et al showed 58% were male, and 42% were female.⁷ The overall indication was most predominantly seen in patients with septic shock, accounting for up to 62.90%, followed by cardiogenic shock, hypovolemic shock, septic/hypovolemic shock, septic/ cardiogenic shock, and other kinds of shock namely neurogenic shock and haemorrhagic shock. These results are consistent with large-scale ICU vasopressor utilisation data, which demonstrate that septic shock accounted for the majority of noradrenaline -requiring cases (roughly 62%), with smaller percentages of cardiogenic and hypovolemic shock, reflecting real clinical practice in a range of critical care settings.⁸

The duration of noradrenaline therapy varied across the study population, ranging from 1 to 12 days, with the majority of the population receiving it for 3 days. This pattern likely reflects early hemodynamic stabilisation in a substantial proportion of patients. The pharmacokinetic characteristics of Norad, including metabolism, excretion, and mode of administration, have a significant impact on its duration of action. Because noradrenaline has a very short plasma half-life of only two to three minutes, its effects only last during or shortly after the infusion, requiring careful monitoring and frequent dose adjustments throughout treatment.

Hemodynamic improvement was particularly reflected by increases in systolic, diastolic, and mean arterial pressure, particularly within the first hour of infusion (T1). Noradrenaline was effective in maintaining a mean arterial pressure above 65 mmHg during therapy and following discontinuation of the drug. The current guidelines, which recommend that patients with septic shock maintain a MAP of at least 65 mmHg, are consistent with the reported improvement in MAP in the current study.⁹

An initial increase in heart rate was observed within the first hour of noradrenaline infusion, which gradually decreased over time. After 24 hours, there was a notable decrease in heart rate, which could be due to improved perfusion, clinical stabilisation, and a gradual tapering of noradrenaline doses after initial resuscitation. The results of this study are in line with those of Hamzaoui et al., who showed that noradrenaline has a beneficial inotropic effect in the early stages of septic shock. According to their research, norepinephrine mainly enhances cardiac function by increasing contractility, with only slight and transient changes in heart rate. Differences in study design, duration of observation, and real-world dose titration may explain variations in heart rate trends beyond the early phase of therapy.¹⁰Central venous administration was the predominant route in this study, which is consistent with standard recommendations for vasopressor therapy, considering the need for continuous infusion and the risk of local tissue injury with peripheral administration.¹¹Although dextrose-containing solutions have historically been suggested as noradrenaline, the use of normal saline in the present study reflects institutional practice and real-world ICU utilisation.¹²

The laboratory improvements occurred alongside overall clinical stabilisation and cannot be attributed solely to noradrenaline therapy. Previous studies show that noradrenaline-induced hemodynamic stability may potentially be associated with improved renal outcomes in septic shock and may not adversely affect renal function.¹³

Numerous possible drug-drug interactions involving noradrenaline were found, and polypharmacy was prevalent. Due to the high prevalence of polypharmacy in critically ill patients, the majority of detected interactions were potential rather than clinically restrictive. The majority were predictable pharmacodynamic interactions that could be controlled with regular monitoring. Similar findings have been reported in other ICU-based drug utilisation studies, where polypharmacy increases the frequency of potential pharmacodynamic interactions. This highlights the importance of medication review and monitoring in the critical care settings.¹⁴

Clinical results varied; some patients showed improvement through discharge or ward transfer, but mortality remained high, indicating the severity of illness in patients in need of vasopressor therapy. Overall, noradrenaline therapy cannot be exclusively attributed to clinical outcomes because concurrent treatments and the severity of the disease probably had an impact.

The observational design, single-centre setting, and inability to standardise dosing in weight-based units are some of the limitations of this study. Additionally, the influence of concurrent therapies and the severity of the illness could not be fully controlled. Despite these limitations, the study provides valuable insight into real-world noradrenaline utilisation and highlights rational prescribing practices, expected hemodynamic effects, and common safety considerations in critically ill patients.

DECLARATION

Ethical approval: This is an observational study, and it did not involve direct patient intervention. As per the institutional policy, formal ethical committee approval was not required.

Funding: None

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