What do we know about this issue?

Which are the new contributions of this study?

INTRODUCTION

Circulatory shock is a pathological condition involving acute circulatory failure, characterized by hypotension, leading to a decrease in tissue perfusion, which if not treated promptly results in multisystem organ failure and potentially death ^1,2. Circulatory shock is one of the main causes for admission to the intensive care unit, representing around 33% of ICU patients³. Among the different types of shock, the most common is distributive septic shock which accounts for 62 % of the ICU patients⁴, with mortality rates ranging between 46 and 60 % ^5,6. A study conducted in various ICUs in Colombia found that 12 % of the patients were diagnosed with sepsis, with a high overall mortality of 34 % ⁷.

The ICU stay costs in Colombia are around 400 USD per day (1 USD = 3.281 COP, based on the representative market exchange rate, December 2020. Banco de la República de Colombia), or higher, when considering the medications these patients require ^8,9. Vasopressors, introduced in the 1940's are one of the most widely used drugs in the ICU ¹. Due to their vasoconstrictive properties, they are often used in critical care for cardiopulmonary resuscitation, postoperative heart surgery care, and the management of hypotension associated with the different types of shock, in order to improve the hemodynamic function and restore tissue perfusion, and hence improving tissue oxygen delivery ^1,10,11. The main drugs with vasopressor activity used in the ICU may be classified into two groups: the non-adrenergic agents (vasopressin) and the adrenergic agents (adrenaline, norepinephrine, dopamine, ephedrine, etilefrine and phenylephrine) ^12,13.

The choice of a vasopressor and its dose depends on the shock etiology and the clinical context of each patient ^1,10. While historically there has been a controversy with regards to the choice of the most appropriate vasopressor for managing septic shock ¹⁴, currently, the international guidelines of the Surviving Sepsis Campaign recommend norepinephrine as the first line drug, based on its effectiveness and lower incidence of adverse cardiovascular effects ^2-4,11,14-16. Likewise, norepinephrine is used as the last resort for the management of neurogenic and hemorrhagic shock ^17,18. With regards to cardiogenic shock, according to the most current European Guidelines, norepinephrine is considered the first choice, usually combined with an inotropic support therapy, and dobutamine is the most widely used drug for this purpose ¹⁹. Furthermore, adrenaline is considered the first choice in anaphylactic shock, due to its sympathomimetic and anti-inflammatory properties ²⁰.

Considering that in our region few studies focus on this topic, and due to the significant importance of shock and vasopressor management, the purpose of the study was to establish the trends in the use of vasopressors in the ICU, in a population of patients affiliated to the Colombian Healthcare System between 2010 and 2017.

PATIENTS AND METHODS

A descriptive, observational study was conducted on the trends in the use of vasopressors in eleven Colombian ICUs, based on the vasopressors dispensed by the logistics operator of medications at the hospital and outpatient level. The records and various variables are systematically stored in an electronic database. All of the medications dispensed in-hospital in the institutions studied, were administered by this sole operator. The data from patients over 18 years old, both males and females, affiliated with the Colombian Healthcare system who received any vasopressor during their ICU admission from January 2010 through December 2017 were included. Any incomplete records, as well as records associated directly with the ICU instead of a particular patient, were excluded. The study included the dispensing records of vasopressors effectively administered to patients.

Based on the information recorded on the use of medications, a data base was developed to analyze the following variables:

The monthly dispensing with the respective doses to quantify use was analyzed, and the daily defined dose (DDD) was used as the technical unit to quantify use expressed as DDD/100 beds/day (DBD), in accordance with the recommendation of the World Health Organization (WHO), as the standard to conduct pharmaco-epidemiological studies. The DDD value is the average daily dose estimated for the primary indication of the drug, and the WHO Anatomical, Therapeutical, Chemical Classification System index - ATC/DDD -was obtained for each of the study drugs ²¹. The following formula was used to calculate the DBD ²²:

Additionally, the vasopressor utilization index (VUI) was estimated as a specific measure used to describe the use of these medications, according to the following formula ^1,23:

The database was reviewed and validated by the Pharmacoepidemiology department of the logistics operator. The statistical package SPSS, version 24.0 (IBM, USA) for windows was used for the data analysis. Descriptive statistics was used to estimate averages, standard deviations, minimum and maximum values for continuous variables and percentages for categorical variables. The percentage annual change of variation for each DBD value was estimated, as well as the percentage global change comparing 2017 and 2010 [Change = (final value - initial value) / (initial value)]. The DBD difference was also estimated between the 2017 and 2010 values [Difference = final valor - initial value].

The study was approved by the Bioethics Committee of the Universidad Tecnológica de Pereira in the "no risk category" (approval number: CBE-SYR-162016, August 10, 2017). No personal patient data were used, and the principles enshrined in the Declaration of Helsinki were followed.

RESULTS

Between January 2010 and December 31 2017, a total of 19,186 patients received treatment with vasopressors in the mixed ICUs of eleven hospitals in seven Colombian cities (Table 1). The mean age of patients was 66.3 ± 18.1 years and 52.6 % (n = 10,097) were males. The cities with the largest number of patients cared for were Bogotá (n = 7,054; 36.8 %), Cali (n = 4,735; 24.7 %) and Manizales (n = 3,348; 17.5 %). The ICUs studied had 16.0 ± 7 beds in average.

26,414 treatments were administered in the study population, for a total of 81,348 doses of vasopressors dispensed. The mean treatment duration was 1 day (IQR: 1-3). The vasopressor with the largest proportion of doses dispensed in average during the 8 years of follow-up was norepinephrine (76.0 %), followed by adrenaline (26.6 %), dopamine (19.4 %) and dobutamine (16.0 %). The proportion of use of each of the medications studied over time is shown in Table 1.

The trends over time of the DBD for the vasopressor used are shown in Table 2. For 2017, the most frequently used drugs based on the DBD were norepinephrine (59.9 DBD), adrenaline (32.0 DBD) and dobutamine (1.5 DBD). During the time under observation, only norepinephrine experienced a rise in its use (+6.19 DBD); on the other hand, adrenaline and dopamine were the drugs with the highest reduction in use (-60.6 and -10.8 DBD, respectively) (Table 2). Changes in DBD are shown in Figure 1. Additionally, Table 3 depicts the annual evolution of the VUI for each molecule used.

SOURCE: Authors.

FIGURE 1 Trend of the daily doses defined per 100 beds/day of each drug between 2010 and 2017 in patients admitted to ICUs in Colombia. 

Monotherapy versus combined therapy

Of the total number of treatments recorded in the trial, 17,658 (66.8 %) were with just one vasopressor and 8,756 (33.2 %) with a combination of vasopressors.

Of these latter treatments, 6,117 (23.1 %) treatments included two drugs; 2,090 (7.9 %) included three drugs; and 549 (2.1 %) received between four to six vasopressors. Norepinephrine was used mostly in combined therapy (60.1 %), while adrenaline, dopamine, dobutamine and vasopressin were mainly administered as monotherapy (Figure 2). The most frequently used combinations were adrenaline with norepinephrine (n = 4,535; 51.8 % of the combined therapies), norepinephrine with dobutamine (n = 2,575; 29.4 %), norepinephrine with dopamine (n = 2,256; 25.8 %) and vasopressin with norepinephrine (n = 1,949; 22.3 %).

SOURCE: Authors.

FIGURE 2 Therapies with the main study vasopressors used and their distribution based on administration as monotherapy or combined therapy in the study, in eleven ICUs in Colombia (2010-2017). 

DISCUSSION

This study evidenced an incremental trend in the use of norepinephrine between 2010 and 2017 in the mixed ICUs in eleven hospitals in Colombia, making it the most frequently used vasopressor during the study period, followed by adrenaline and dopamine. This is probably due to the development of further scientific evidence supporting the early use of norepinephrine in the vasoplegic patient ^{3,4,11,18,19,24} and its subsequent inclusion in the list of medications in the Colombian Healthcare System Benefit Plan.

Vasoactive drugs, and in general those with a vasopressor effect, are essential as first line therapies for the management of distributive shock conditions, such as septic shock, considered one of the most severe public health problems, representing in average a mortality rate of 25.8 % in the ICU worldwide ²⁵. A multicenter epidemiological study in Colombia reported a 28-day mortality rate of 45.6 % for patients admitted with septic shock ²⁶; this data emphasize the relevance of learning about the trends in the use of vasopressors and a comparison with the rest of the world.

Norepinephrine seems to be the most frequently used vasopressor in the ICU worldwide ^1-4,11. This is consistent with a study conducted by Thongprayoon et al., which established the trend in the use of vasopressors in the ICU of a reference medical center in the United States between 2007 and 2013, evidencing that the trend in the use of norepinephrine showed the highest increase in the period studied and became the most widely used vasopressor for the management of septic shock ¹. Jentzer et al. described similar patterns, with an increase of norepinephrine use in ICU patients with heart conditions in the United States, with a decrease in the use of dopamine, during the period from 20072015 ²⁷.

With regards to the VUI values, similar trends and values to those described in medical and mixed ICUs were identified in the United States. For example, norepinephrine during the last few years studied, reached VIU values above 0.8, whilst adrenaline fell below 0.2 (1.23). These changes are not found in other types of ICUs, such as those focused in managing patients with surgical cardiac pathology in whom the main vasopressor according to the VUI was adrenaline ¹.

Moreover, the data obtained in this analysis indicate the clear impact of scientific evidence over the last few years, in the management of vasopressors; it is clear that the ICU practitioners have followed the recommendations of the international guidelines of the Surviving Sepsis Campaign, encouraging the use of norepinephrine as a first line vasopressor for the management of septic shock ^11,16,28; as well as the information derived from recent studies evidencing the increasing effectiveness in terms of reduced mortality and higher safety offered by this medication as compared against dopamine or adrenaline ^3,4,24,27. In this paper it was not possible to establish the diagnosis of the patients that required a vasopressor; however, norepinephrine, besides being the drug of choice in septic shock, is also widely recommended for other types of shock such as cardiogenic, neurogenic and even hypovolemic shock and this fact may also account for its increased used over the years ^11,18,19.

Dopamine was the vasopressor with the most significant reduction in use in the ICUs, probably as a result of the SOAP-II trial ⁴ and a meta-analysis by De Backer et al. in 2012, in which dopamine was compared against norepinephrine for the management of septic shock; they found that the use of dopamine was associated with a higher mortality and incidence of arrhythmia ²⁹.

Vasopressin as monotherapy was relatively stable in the series studied and currently its use focuses on reducing the doses of noradrenaline and as a pharmacological adjuvant in case of failure to achieve the mean arterial pressure goals ¹¹. The studies with vasopressin recommend using the drug mostly in cases of septic shock, with less evidence in other types of shock ^2,18-20,30.

With regards to combined therapy, adrenaline which was most frequently associated with norepinephrine in this series (52 % of the combined therapies) could be the result of the recommendations of the guidelines of the Surviving Sepsis Campaign, considering it an option for use in combination with norepinephrine to increase the mean arterial pressure ¹¹. However, this association may change in the future because of new evidence in favor of the combination of norepinephrine with vasopressin ¹¹.

This study presents some limitations because the information was taken from a database of drug dispensation directly to hospital institutions, and the patients' medical records were not reviewed, neither was it possible to establish the diagnosis for which the patient received the medication. The clinical outcomes data, or the effectiveness of various therapies were also missing. Some of the aspects to be highlighted include a detailed report of the use of the medications over time for a specific healthcare service, and on an individualized basis for each patient. The results are only applicable to patients with similar healthcare and insurance characteristics.

CONCLUSION

Based on the previous findings it may then be concluded, that the most frequently used vasopressor in the ICUs of the participating institutions was norepinephrine, a fact that is supported by the evidence in favor of its effectiveness and safety in patients with shock. It is important to conduct further studies considering these aspects to ensure the best possible quality of care for patients in critical conditions.

ETHICAL RESPONSIBILITIES

Endorsement of the ethics committee. This study was approved by the Bioethics Committee of the Universidad Tecnológica de Pereira, at a meeting held on august 10, 2017, as reported in minutes CBE-SYR-162016.

Protection of persons and animals. The authors declare that no experiments in human beings or animals were conducted for this research and that the procedures followed were consistent with the ethical standards of the human experimentation committee and with the World Medical Association and the Declaration of Helsinki.

Confidentiality of the data. The authors declare that they have followed the protocols of their work institution on the publication of patient data.

ACKNOWLEDGEMENTS