Acessibilidade / Reportar erro

In(compatibility) of intravenous drugs in critical units: adult cohort

In(compatibilidad) de medicamentos intravenosos en unidades críticas: cohorte de adultos

ABSTRACT

Objectives:

To analyze potential (in)compatibilities of intravenous drugs based on the scheduling prepared by the nursing team.

Methods:

historic cohort (retrospective) with 110 adults in critical units. Intravenous medications were identified concomitantly, whose pairs were analyzed for (in) compatibility using the screening system Trissel’s™ 2 Compatibility IV-Micromedex 2.0. Parametric and non-parametric statistic were used according to the nature of the variable.

Results:

565 pairs of drugs were identified. Of these, 44.9% were compatible; and 8.8%, potentially incompatible. Most potentially incompatible pairs involved substances with alkaline pH such as phenytoin (32%) and sodium bicarbonate (8%) and weak acids such as midazolam (12%) and dobutamine (6%), which could result in precipitate formation.

Conclusions:

almost half of the mixtures simultaneously administrated was compatible, which indirectly reflects in the organized work between the nursing team and the clinical pharmaceutic in the discussions and decisions related to time scheduling.

Descriptors:
Intravenous Administration; Incompatibility of Drugs; Intensive Care Units; Critical Care Nursing; Nursing Education

RESUMEN

Objetivos:

analizar las (in)compatibilidades potenciales de medicamentos intravenosos basado en el aplazamiento de horarios realizado por equipo de enfermería.

Métodos:

cohorte histórica (retrospectiva) con 110 adultos de unidades críticas. Identificaron medicamentos intravenosos aplazados de modo concomitante, cuyas duplas han analizadas cuanto a la (in)compatibilidad por medio del sistema de screening Trissel’s™ 2 Compatibility IV-Micromedex 2.0. Utilizó estadística paramétrica y no paramétrica segundo naturaleza de la variable.

Resultados:

identificaron 565 duplas de medicamentos. De estas, 44,9% compatibles; y 8,8%, potencialmente incompatibles. Mayoría de las duplas potencialmente incompatibles envolvió substancias con pH alcalino como fenitoína (32%) y bicarbonato de sodio (8%) y ácidos débiles como midazolam (12%) y dobutamina (6%), las cuales podrían resultar en precipitación.

Conclusiones:

casi mitad de las misturas aplazadas simultáneamente fue compatible, aspecto que, indirectamente, refleja el trabajo orquestado entre el equipo de enfermería y el farmacéutico clínico en las discusiones y decisiones acerca del aplazamiento de horarios.

Descriptores:
Administración Intravenosa; Incompatibilidad de Medicamentos; Unidades de Cuidados Intensivos; Enfermería de Cuidados Críticos; Educación en Enfermería

RESUMO

Objetivos:

analisar as (in)compatibilidades potenciais de medicamentos intravenosos com base no aprazamento de horários realizado pela equipe de enfermagem.

Métodos:

coorte histórica (retrospectiva) com 110 adultos de unidades críticas. Identificaram-se medicamentos intravenosos aprazados de modo concomitante, cujas duplas foram analisadas quanto à (in)compatibilidade por meio do sistema de screening Trissel’s™ 2 Compatibility IV-Micromedex 2.0. Utilizou-se estatística paramétrica e não paramétrica segundo natureza da variável.

Resultados:

identificaram-se 565 duplas de medicamentos. Destas, 44,9% foram compatíveis; e 8,8%, potencialmente incompatíveis. A maioria das duplas potencialmente incompatíveis envolveu substâncias com pH alcalino como fenitoína (32%) e bicarbonato de sódio (8%) e ácidos fracos como midazolam (12%) e dobutamina (6%), as quais poderiam resultar em precipitação.

Conclusões:

quase metade das misturas aprazadas simultaneamente foi compatível, aspecto que, indiretamente, reflete o trabalho orquestrado entre a equipe de enfermagem e o farmacêutico clínico nas discussões e decisões acerca do aprazamento de horários.

Descritores:
Administração Intravenosa; Incompatibilidade de Medicamentos; Unidades de Terapia Intensiva; Enfermagem de Cuidados Críticos; Educação em Enfermagem

INTRODUCTION

In different assistance scenarios, the safe use of medications is considered, by the World Health Organization (WHO), the third global challenge within the scope of the patient safety. Costs related to damage caused by Medication Errors (ME) are worldly estimate in US$ 42 billion a year(11 World Health Organization (WHO). Global Patient safety challenge. medication without harm. [Internet]. Geneva: WHO; 2017 [cited 2018 Sep 27]. Available from: https://apps.who.int/iris/bitstream/handle/10665/255263/WHO-HIS-SDS-2017.6-eng.pdf;jsessionid=060E7EB97B61CF3ADC23C315D911AE99?sequence=1
https://apps.who.int/iris/bitstream/hand...
). Unsafe practices related to drug administration, including infusion of incompatible intravenous drugs (IV), represent one of the most drug-related adverse events (AME) more frequent during hospitalization, and can result in irreversible damages, which most of the time are avoidable(22 Fahimi F, Ariapanah P, Faizi M, Shafaghi B, Namdar R, Ardakani MT. Errors in preparation and administration of intravenous medications in the intensive care unit of a teaching hospital: an observational study. Aust Crit Care. 2008;21(2):110-6. https://doi.org/10.1016/j.aucc.2007.10.004
https://doi.org/10.1016/j.aucc.2007.10.0...
).

Incompatibility between medications (IN) occurs when two or more drugs are combined in the same solution or receptacle and cause an adverse physic-chemical phenomenon, whose final product can show modification in its physical state(33 Newton DW. Physicochemical determinants of incompatibility and instability in injectable drug solutions and admixtures. Am J Hosp Pharm. 1978;35(10):1213-22.). Simultaneous infusions of incompatible medications can result in the administration of underdose of drugs; in obstruction of catheters, with consequent loss of intravenous device; in the formation of precipitates that can cause phlebitis or pulmonary thromboembolism; in the evolution to septic conditions; or death(44 Secoli SR. Drugs interactions: fundamental aspects for clinical practice nursing. Rev Esc Enferm USP. 2001;35(1):28-34. https://doi.org/10.1590/S0080-62342001000100005 Portuguese.
https://doi.org/10.1590/S0080-6234200100...

5 Kanji S, Lam J, Goddard R, Johanson C, Singh A, Petrin L, et al. Inappropriate medication administration practices in Canadian Adult ICUs: a multicenter, cross-sectional observational study. Ann Pharmacother. 2013;47(5):637-43. https://doi.org/10.1345/aph.1R414
https://doi.org/10.1345/aph.1R414...

6 Kanji S, Goddard R, Donnely R, McIntyre L, Turgeon A, Coons P, et al. Physical compatibility of drug infusions used in Canadian Intensive Care Units: a program of research. Crit Care Med. 2010;38(9):1890-8. https://doi.org/10.1097/CCM.0b013e3181e8adcc
https://doi.org/10.1097/CCM.0b013e3181e8...

7 Benlabed M, Perez M, Gaudy R, Genay S, Lannoy D, Barthélémy C, et al. Clinical implications of intravenous drug incompatibilities in critically ill patients. Anaesth Crit Care Pain Med. 2019;38(2):173-80. https://doi.org/10.1016/j.accpm.2018.04.003
https://doi.org/10.1016/j.accpm.2018.04....
-88 Benlabed M, Mena AM, Gaudy R, Perez M, Genay S, Hecq JD, et al. Analysis of particulate exposure during continuous drug infusion in critically ill adult patients: a preliminary proof-of concept in vitro study. Intensive Care Med Exp. 2018;6:38. https://doi.org/10.1186/s40635-018-0205-2
https://doi.org/10.1186/s40635-018-0205-...
). This way, an IN can compromise the therapeutic efficacy of the drug and affect the clinical stability of critical patients, especially because many drugs have dose-dependent effects(77 Benlabed M, Perez M, Gaudy R, Genay S, Lannoy D, Barthélémy C, et al. Clinical implications of intravenous drug incompatibilities in critically ill patients. Anaesth Crit Care Pain Med. 2019;38(2):173-80. https://doi.org/10.1016/j.accpm.2018.04.003
https://doi.org/10.1016/j.accpm.2018.04....
,99 Maiguy-Foinard A, Genay S, Lannoy D, Barthélémy C, Lebuffe G, Debaene B, et al. Criteria for choosing an intravenous infusion line intended for multidrug infusion in anaesthesia and intensive care units. Anaesth Crit Care Pain Med. 2017;36(1):53-63. https://doi.org/10.1016/j.accpm.2016.02.007
https://doi.org/10.1016/j.accpm.2016.02....
).

Critical patients are highly vulnerable to IN. The severity and instability of clinical conditions, the complexity of therapeutic regime, the coadministration of drugs with different osmolarity and hydrogen potential (pH), superimposed on the limited number of venous accesses or catheter routes, contribute to the occurrence of IN(44 Secoli SR. Drugs interactions: fundamental aspects for clinical practice nursing. Rev Esc Enferm USP. 2001;35(1):28-34. https://doi.org/10.1590/S0080-62342001000100005 Portuguese.
https://doi.org/10.1590/S0080-6234200100...

5 Kanji S, Lam J, Goddard R, Johanson C, Singh A, Petrin L, et al. Inappropriate medication administration practices in Canadian Adult ICUs: a multicenter, cross-sectional observational study. Ann Pharmacother. 2013;47(5):637-43. https://doi.org/10.1345/aph.1R414
https://doi.org/10.1345/aph.1R414...
-66 Kanji S, Goddard R, Donnely R, McIntyre L, Turgeon A, Coons P, et al. Physical compatibility of drug infusions used in Canadian Intensive Care Units: a program of research. Crit Care Med. 2010;38(9):1890-8. https://doi.org/10.1097/CCM.0b013e3181e8adcc
https://doi.org/10.1097/CCM.0b013e3181e8...
,1010 Secoli SR, Pérez-Esquirol E, Heras-Matellán MJ, Vendrell-Bosh L, Ballarín-Alins E. Incompatibilidades em la terapia intravenosa: ¿quéhacer para preveni-las? Enferm Clín. 2009;19(6):349-53. https://doi.org/10.1016/j.enfcli.2009.07.003 Spanish.
https://doi.org/10.1016/j.enfcli.2009.07...

11 Moraes CG, Silva D, Bueno D. Análise de incompatibilidades de medicamentos intravenosos no Centro de Tratamento Intensivo adulto do Hospital das Clínicas de Porto Alegre. Rev HCPA [Internet]. 2011[ cited 2020 Feb 27];31(1):31-8. Available from: https://seer.ufrgs.br/hcpa/article/view/14733/11591 Portuguese.
https://seer.ufrgs.br/hcpa/article/view/...

12 Machotka O, Manak J, Kubena A, Vlcek J. Incidence of intravenous drug incompatibilities in intensive care units. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159(4):652-6. https://doi:10.5507/bp.2014.057
https://doi:10.5507/bp.2014.057...
-1313 Silva LD, Matos GC, Barreto BG, Albuquerque DC. Drug scheduling for nurses in prescriptions at sentinela hospital. Texto Contexto Enferm. 2013;22(3):722-30. https://doi: 10.1590/S0104-07072013000300019.
https://doi:...
).

In addition, there is the problem with medication administration schedules concurrently(1010 Secoli SR, Pérez-Esquirol E, Heras-Matellán MJ, Vendrell-Bosh L, Ballarín-Alins E. Incompatibilidades em la terapia intravenosa: ¿quéhacer para preveni-las? Enferm Clín. 2009;19(6):349-53. https://doi.org/10.1016/j.enfcli.2009.07.003 Spanish.
https://doi.org/10.1016/j.enfcli.2009.07...
,1414 Paes GO, Moreira SO, Moreira MB, Martins TG. Drug incompatibility in the ICU: review of implications in nursing practice. Rev Eletrôn Enferm. 2017;19:a20 https://doi.org/10.5216/ree.v19.38718
https://doi.org/10.5216/ree.v19.38718...
). Studies show that scheduling performed by the nursing team describe a concentration of drugs in certain schedules, which seems related to the institutional routine. Regardless of the route of administration or pharmacological action, medication administration schedules seem to occur invariably in different service(1313 Silva LD, Matos GC, Barreto BG, Albuquerque DC. Drug scheduling for nurses in prescriptions at sentinela hospital. Texto Contexto Enferm. 2013;22(3):722-30. https://doi: 10.1590/S0104-07072013000300019.
https://doi:...
,1515 Amorim FDB, Flores PVP, Bosco PS, Menezes AHB, Alóchio KV. O aprazamento de medicamentos pautados na segurando paciente: um alerta para prática de enfermagem. Rev Enferm UFPE. 2014;8(1):224-8. https://doi.org/10.5205/reuol.4843-39594-1-SM.0801201432 Portuguese.
https://doi.org/10.5205/reuol.4843-39594...
-1616 Fonseca RB, Secoli SR. Drugs used in bone marrow transplantation: a study about combinations of potentially interactive antimicrobials. Rev Esc Enferm USP. 2008;42(4):706-14. https://doi.org/10.1590/S0080-62342008000400013
https://doi.org/10.1590/S0080-6234200800...
). This practice to adopting standard schedules, usually even hours (h) – 8, 10, 12, 14, 16, 18, 20, 22, 0, 2, 4, and 6h –, distant from shift changes and visiting hours may cause IN, since variables that interfere with its occurrence are disregarded, such as the pH of medicines, manufacturers of products, type of diluent and infusion, final concentration of the mixture, time of contact between drugs, conditions for preparing medicines (temperature and light) and the use of a multi-lumen device (e.g., Y)(1414 Paes GO, Moreira SO, Moreira MB, Martins TG. Drug incompatibility in the ICU: review of implications in nursing practice. Rev Eletrôn Enferm. 2017;19:a20 https://doi.org/10.5216/ree.v19.38718
https://doi.org/10.5216/ree.v19.38718...
).

Due to the importance of drugs administration scheduling in the precipitate formation of IN, and due to the leadership of nursing team, the present study was elaborated.

OBJECTIVES

Tp analyze potential (in)compatibilities of intravenous drugs (IPM) based on the scheduling prepared by the nursing team when admitting and releasing patients hospitalized in critical care units.

METHODS

Ethical aspect

This survey is part of the study “Patients Safety in Intensive Care Units”, which goal was analyzing the influence of distinct variables (patients, human resources, safety culture) in the occurrence of adverse events in critical units(1717 Padilha KG, Barbosa RL, Oliveira EM, Andolhe R, Ducci AJ, Secoli SR Patient safety in Intensive Care Units: development of a research Project. Rev Esc Enferm USP. 2015;49(N-Esp):157-63. https://doi.org/10.1590/S0080-623420150000700022
https://doi.org/10.1590/S0080-6234201500...
). This way, the project is in accordance with the Guidelines of the Resolution 466/12 of National Health Council (CNS), being approved by the Research Ethics Committee of the Academic Hospital of São Paulo University (HU-USP).

Design, period and place of study

The study consists of a historic cohort (retrospective) of adult patients hospitalized in critical unities (Intensive Care Unit – ICU; and Semi-Intensive – SI) of an Academic Hospital in the city of São Paulo. This is a general hospital, which medical and hospital care has medium complexity. The critical unities, dedicate to adult care submitted to clinic and/or surgical care, have the total of 20 beds, 12 of which are for ICU, and 8 are for SI(1818 Universidade de São Paulo. Hospital Universitário. Regimento [Internet]. São Paulo; 2012. [cited 2020 Feb 27]. Available from: http://www.hu.usp.br/regimento
http://www.hu.usp.br/regimento...
).

The elaboration of this observational study was sustained by the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.

Population or sample; criteria of inclusion and exclusion

The consecutive sampling was composed by 110 adult patients (≥ 18 years), which used two or more intravenous drugs, who were hospitalized in the period of May to June 2012, with permanence time at ICU or SI higher or equal to 72 hours. The records of patients whose prescription data were incomplete were excluded.

Study protocol

Data was obtained by consulting the original study database of 2015, which allowed the extraction of demographic variables (gender, age), clinics (number of comorbidities, origin, hospitalization unit, type of hospitalization, Simplified Acute Physiology Score II – SAPSII), clinical evolution (medical discharge condition [Survivor or death], Nursing Activities Score – NAS), and variables related to therapeutic regime (number of prescribers, number of drugs prescribed, name of the drugs, scheduling, and day of the prescription [admission and discharge]).

Through medical prescription, IV drugs were simultaneously scheduled (same time), which formed pairs whose (in)compatibility was analyzed. Identifying the (in)compatibility, it was assumed that all IV drugs scheduled at the same time were coadministered in the same route, regardless the number of venous devices. All scheduled drugs were analyzed and administered continuous or intermittently in a Y-device, except crystalloid/colloid solutions and parenteral nutrition.

(In)compatibility was verified through the online software Trissel’s™ 2 Compatibility IV, hosted in the Micromedex 2.0® database, accessed through the portal CAPES – Brazilian Federal Agency for Support and Evaluation of Higher Education(1919 MICROMEDEX Healthcare Series [Internet]. New York; [2021]. Available from: https://www.ibm.com/br-pt/watson-health/about/micromedex [cited 2021 Mar 11].
https://www.ibm.com/br-pt/watson-health/...
).

Drug pairs were analyzed for (in)compatibility in method and infusion by Y-devices and classified as “incompatible”, “variable compatibility” and “untested drugs”. Medicines that show physical-chemical alteration when mixed during infusion in a Y-device are called “incompatible”; “variable compatibility” is attributed when there is a divergence in the results of compatibility between drugs supplied by different manufacturers; and “untested drugs” are those whose drugs have not been tested(2020 Truven Health Analytics. Micromedex solutions(r). Ann Arbor; (c)2014. Chap.11 - IV compatibility tool. p. 131-45.).

Potential incompatibility between drugs (IPM) was considered to be the theoretical possibility of altering the compatibility of drugs resulting from their simultaneous infusion by Y-devices.

A potential incompatibility between the drugs (IPM) and the theoretical possibility of altering the compatibility of such drugs were considered, due to the simultaneous infusion of these by Y-devices.

Analysis of results and statistics

The software R 3.5.1 was used, and the level of significance was established as 5%. In statistic processing, categories variables were presented in tables and graphic (absolute and relative frequencies). For quantitative variables, average and standard deviation (SD) were calculated. Average values were compared by the Wilcoxon, McNemar, and paired T tests. In inferential analysis, data distribution was tested for normality for the selection of parametric or non-parametric tests.

RESULTS

Patients’ characteristics

Most of the patients was male (52.7%; n = 58); patients originated from critical units, operating rooms or first-aid posts (87.2%; n = 96), and hospitalized in ICU (77.3%; n = 85), with clinical diagnosis (61%; n = 67). The average age and length of hospital stay were 62.9 years (±16.3) and 7.2 days (±4.7), respectively. SAPSII score was 48.6 (±24.9); and mortality rate was 14.6% (n = 16) (Table 1).

Table 1
Demographic, clinical and progress characteristics of critical patients - 2015, Academic hospital, São Paulo, São Paulo, Brazil, (N = 110)

Simultaneous drug infusions: admission and discharge

Of the total sample, 41.8% (n = 46) presented simultaneous infusions of drugs that resulted in IPM. Most of these (71.8%; n = 33) presented incompatibility upon admission; 6.5% (n = 3) at discharge; and 21.7% (n = 10) on both days of analysis.

Admission had an average of 1.8 (±1,1) pairs of incompatible drugs; and 2.3 (±1,5) pairs at the moment of the patient’s discharge. Both days the average was 1.7 (±0,5). A significant difference between days was not observed (p = 0.796) (paired T-test).

There was an increased number of prescribed drugs, prescribers, vascular devices, and increased workload in admission compared to the discharge day (Table 2).

Table 2
Therapeutic and progress characteristics of critical patients - 2015, Academic Hospital, São Paulo, São Paulo, Brazil, (N = 110)

Intravenous drugs scheduling

3,772 IV drug doses were scheduled. Most of them (69.5 %; n = 2,625) occurred when the patient was admitted and, among these, half of the doses (51%; n = 1,337) was scheduled in the evening shift (7 pm to 7 am). Upon discharge, more than half of the doses (56.3%; n = 589) was schedule in day shift (7 am to 7 pm).

Analyzing the simultaneous scheduling of medications, 565 distinct pairs were identified. Among them, almost half (44.9%; n = 254) was considered compatible; 26.1% (n = 147) were classified as untested medication; 11.4% (n = 64) presented variable compatibility; 8.8% (n = 50) resulted in “Unavailable information”, and 8.8% (n = 50) were incompatible.

In “Unavailable information” group, drugs that were not identified in the base were included, such as sodium dipyrone (78%; n = 39); glucose 50% (14%; n = 7) and terlipressin (8%; n = 4).

Upon admission, the pairs of incompatible drugs were scheduled, mostly, at 10 am (32%; n = 17) and 4 pm (32%; n = 17). Upon discharge, scheduling was more frequently at 6 am (14%; n = 7) and 8 am (12%; n = 6) (Figure 1).

Figure 1
Infusion schedule for incompatible medication pairs, related to the day they were administered — 2015, Academic Hospital, São Paulo, São Paulo, Brazil, (N = 110)

(In)compatibilities of intravenous drugs

The 50 pairs classified as incompatible were built by infused medications continuously × intermittently (52%; n = 26), such as mixtures involving sedatives and vasoactive drugs with antibiotics, corticosteroids and diuretics; then, intermittently × intermittently (42%; n = 21), such as furosemide and ondansetron; and continuously × continuously (6%; n = 3), as dobutamine × piperacillin + tazobactam.

In the pairs, 40% (n = 20) had substances with basic pH, such as phenytoin (32%; n = 16) and sodium bicarbonate (8%; n = 4); and weak acids, such as midazolam (12%; n = 6) and dobutamine (6%; n = 3).

The combination midazolam × omeprazole was the most frequent in patients (23.9%; n = 11), followed by sodium bicarbonate × norepinephrine (13%; n = 6) and dobutamine × sodium ceftriaxone 10.8% (n = 5). The antibiotics ceftriaxone, clindamycin, piperacillin + tazobactam and cefepime, combined with each other or with other substances, had a frequency of 45.6% (n = 26) (Table 3).

Table 3
Fifteen more frequent pairs of potentially incompatible drugs in critical patients, and the respective potential physical-chemical alterations - 2015, Academic Hospital, São Paulo, São Paulo, Brazil, (N = 110)

The reactions resulting from the IMP identified based on the schedule could result in precipitate formation (50%; n = 25), particle formation and/or color change (20%; n = 10); turbidity (14%; n = 7); chemical decomposition (6%; n = 3); appearance of fog (4%; n = 2), formation of free oil in the emulsion (4%; n = 2) and change in color (2%; n = 1).

Phenytoin coadministered with 16 different drugs - among the alkaline, furosemide, imipenem + cisplatin and thiopental; and acids, ceftriaxone, clindamycin, dobutamine, dopamine, fentanyl, insulin, methylprednisolone, midazolam, sodium nitroprusside, piperacillin + tazobactam, ranitidine, thiamine, vancomycin - could result in precipitate formation in all mixtures.

DISCUSSION

Potential incompatibility between drugs

The administration of IV drugs with simultaneous schedules in critical units, which included the analysis of 3,772 doses, was higher upon the admission of the patient and preferentially occurred from 10 am to 4pm. Almost half of pairs of infused drugs was compatible (44.9%). Among the incompatible (8,8%), drugs with extreme pH (4.5 ≤ pH ≥ 12.0) were the most involved in the phenomenon, which would potentially cause precipitate reactions.

In this cohort, the predominance of IV drugs upon admission can be attributed to the clinical severity of the patient, expressed by the highest mortality score (SAPSII), average age (> 60 years), higher number of prescribers and presence of IV polypharmacy. Most of the patients (60%) received continuous infused drugs by means of a limited number of venous access (1.9 average), which aspect, in theory, could increase the possibility of potential incompatibility between drugs. The insufficient number of IV devices, often seen in critical units(2121 Fernández-Ruiz M, Carretero A, Díaz D, Fuentes C, González JI, García-Reyne A, et al. Hospital-wide survey of the adequacy in the number of vascular catheters and catheter lumens. J Hosp Med. 2014;9(1):35-41. https://doi.org/10.1002/jhm.2130
https://doi.org/10.1002/jhm.2130...
), represent a risk for IPM, especially if superimposed on the infusion mode(55 Kanji S, Lam J, Goddard R, Johanson C, Singh A, Petrin L, et al. Inappropriate medication administration practices in Canadian Adult ICUs: a multicenter, cross-sectional observational study. Ann Pharmacother. 2013;47(5):637-43. https://doi.org/10.1345/aph.1R414
https://doi.org/10.1345/aph.1R414...
).

In accordance with other authors, the continuous infusion predominated in the sample(55 Kanji S, Lam J, Goddard R, Johanson C, Singh A, Petrin L, et al. Inappropriate medication administration practices in Canadian Adult ICUs: a multicenter, cross-sectional observational study. Ann Pharmacother. 2013;47(5):637-43. https://doi.org/10.1345/aph.1R414
https://doi.org/10.1345/aph.1R414...
-66 Kanji S, Goddard R, Donnely R, McIntyre L, Turgeon A, Coons P, et al. Physical compatibility of drug infusions used in Canadian Intensive Care Units: a program of research. Crit Care Med. 2010;38(9):1890-8. https://doi.org/10.1097/CCM.0b013e3181e8adcc
https://doi.org/10.1097/CCM.0b013e3181e8...
,1111 Moraes CG, Silva D, Bueno D. Análise de incompatibilidades de medicamentos intravenosos no Centro de Tratamento Intensivo adulto do Hospital das Clínicas de Porto Alegre. Rev HCPA [Internet]. 2011[ cited 2020 Feb 27];31(1):31-8. Available from: https://seer.ufrgs.br/hcpa/article/view/14733/11591 Portuguese.
https://seer.ufrgs.br/hcpa/article/view/...
,1414 Paes GO, Moreira SO, Moreira MB, Martins TG. Drug incompatibility in the ICU: review of implications in nursing practice. Rev Eletrôn Enferm. 2017;19:a20 https://doi.org/10.5216/ree.v19.38718
https://doi.org/10.5216/ree.v19.38718...
,2222 Marsilio NR, Silva D, Bueno D. Drug incompatibilities in the adult intensive care unit of a university hospital. Rev Bras Ter Intensiva. 2016;28(2):147-53. https://doi:10.5935/0103-507X.20160029
https://doi:10.5935/0103-507X.20160029...
-2323 Gaetani M, Frndova H, Seto W, Parshuram, C. Concurrent intravenous drug administration to critically ill children: evaluation of frequency and compatibility. J Crit Care. 2017.41:198-203. https://doi.org/10.1016/j.jcrc.2017.05.027
https://doi.org/10.1016/j.jcrc.2017.05.0...
). This very useful way of administration in critical care context was preferably used for short biological half-life drugs (catecholamines) or for those who require constant blood concentration (fentanyl + midazolam). This strategy that promotes the mixture of medications, usually for a contact time of hours, may result in IPM, especially in the presence of a mixture of agents with acid and alkaline pH, some evidenced in this cohort. Drug pairs continuously infused and usually involved in IPM, were used, mainly for patient sedation, a plausible finding with the care environment and recommended by international guidelines(2424 Devlin JW, Skrobik Y, Gélinas C, Needham DM, Slooter AJC, Pandharipande PP et al. Clinical practice guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult patients in the ICU. Crit Care Med. 2018;46(9):825-73. https://doi.org/10.1097/CCM.0000000000003299
https://doi.org/10.1097/CCM.000000000000...
).

Another aspect that deserves special consideration is regarding the possibility of IPM, specially for the direct involvement of the nurse, concerns the schedules when the medications were programmed simultaneously. Most of the doses were scheduled to 10 am, 4 pm, and 2 am and 6pm. The concentration of drugs administration at the times analyzed (admission and discharge), was corroborated by previous studies conducted in critical units, which, similar to this cohort, also did not observe the use of odd hours as a routine for drugs administration(22 Fahimi F, Ariapanah P, Faizi M, Shafaghi B, Namdar R, Ardakani MT. Errors in preparation and administration of intravenous medications in the intensive care unit of a teaching hospital: an observational study. Aust Crit Care. 2008;21(2):110-6. https://doi.org/10.1016/j.aucc.2007.10.004
https://doi.org/10.1016/j.aucc.2007.10.0...
,1313 Silva LD, Matos GC, Barreto BG, Albuquerque DC. Drug scheduling for nurses in prescriptions at sentinela hospital. Texto Contexto Enferm. 2013;22(3):722-30. https://doi: 10.1590/S0104-07072013000300019.
https://doi:...
,2222 Marsilio NR, Silva D, Bueno D. Drug incompatibilities in the adult intensive care unit of a university hospital. Rev Bras Ter Intensiva. 2016;28(2):147-53. https://doi:10.5935/0103-507X.20160029
https://doi:10.5935/0103-507X.20160029...
,2525 Fontenele RE, Araújo TI. Análise de planejamento dos horários de administração de medicamentos em unidades de terapia intensiva cardiológica. Rev Enferm UERJ [Internet]. 2006 [cited 2020 Feb 27];14(3):342-9. Available from: www.revenf.bvs.br/pdf/reuerj/v14n3/v14n3a03.pdf
www.revenf.bvs.br/pdf/reuerj/v14n3/v14n3...
-2626 Fahimi, F, Forough AS, Taghikhani S, Saliminejad L. The rate of physicochemical incompatibilities, administration errors. Factors correlating with nurses' errors. Iran J Pharm Res [Internet]. 2015 [cited 2020 Feb 27];14(Suppl):87-93. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499430/pdf/ijpr-14-087.pdf
https://www.ncbi.nlm.nih.gov/pmc/article...
). The standardization of schedules, even though it favors the organization of the service and is adapted to institutional routines such as logistics for the distribution of medicines by the pharmacy and nursing assistance, can limit the analysis and critical judgment of the nurse regarding the peak of action, drugs physical- chemistry characteristics, drug interactions and potential IPMs(1313 Silva LD, Matos GC, Barreto BG, Albuquerque DC. Drug scheduling for nurses in prescriptions at sentinela hospital. Texto Contexto Enferm. 2013;22(3):722-30. https://doi: 10.1590/S0104-07072013000300019.
https://doi:...

14 Paes GO, Moreira SO, Moreira MB, Martins TG. Drug incompatibility in the ICU: review of implications in nursing practice. Rev Eletrôn Enferm. 2017;19:a20 https://doi.org/10.5216/ree.v19.38718
https://doi.org/10.5216/ree.v19.38718...
-1515 Amorim FDB, Flores PVP, Bosco PS, Menezes AHB, Alóchio KV. O aprazamento de medicamentos pautados na segurando paciente: um alerta para prática de enfermagem. Rev Enferm UFPE. 2014;8(1):224-8. https://doi.org/10.5205/reuol.4843-39594-1-SM.0801201432 Portuguese.
https://doi.org/10.5205/reuol.4843-39594...
,2525 Fontenele RE, Araújo TI. Análise de planejamento dos horários de administração de medicamentos em unidades de terapia intensiva cardiológica. Rev Enferm UERJ [Internet]. 2006 [cited 2020 Feb 27];14(3):342-9. Available from: www.revenf.bvs.br/pdf/reuerj/v14n3/v14n3a03.pdf
www.revenf.bvs.br/pdf/reuerj/v14n3/v14n3...
).

Regarding the performance of the organization of the schedule, almost half of the paired infused drugs was compatible. This dissonant finding from previous studies conducted in ICU, which indicate lower compatibility frequency (21.5%)(1111 Moraes CG, Silva D, Bueno D. Análise de incompatibilidades de medicamentos intravenosos no Centro de Tratamento Intensivo adulto do Hospital das Clínicas de Porto Alegre. Rev HCPA [Internet]. 2011[ cited 2020 Feb 27];31(1):31-8. Available from: https://seer.ufrgs.br/hcpa/article/view/14733/11591 Portuguese.
https://seer.ufrgs.br/hcpa/article/view/...
), may be attributed to some scenario particularities of the study. At investigated units, the clinical pharmacist evaluates the medical prescriptions daily, in order to identify potential issues related to the drugs, such as drugs interactions and IPM. Interventions performed by pharmacists, which include adjustments to the programmed schedule of prescriptions, alteration of the medication infusion mode or a new suggestion for the combination of pairs in the venous access devices, may contribute to the reduction of IPM(1111 Moraes CG, Silva D, Bueno D. Análise de incompatibilidades de medicamentos intravenosos no Centro de Tratamento Intensivo adulto do Hospital das Clínicas de Porto Alegre. Rev HCPA [Internet]. 2011[ cited 2020 Feb 27];31(1):31-8. Available from: https://seer.ufrgs.br/hcpa/article/view/14733/11591 Portuguese.
https://seer.ufrgs.br/hcpa/article/view/...
,2727 Araujo EO, Viapiana M, Domingues EAM, Oliveira GS, Polisel CG. Pharmaceutical interventions in a Intensive Care of a University Hospital. Rev Bras Farm Hosp Serv Saude. 2017;8(3):25-30. https://doi:10.30968/rbfhss.2017.083.005 Portuguese.
https://doi:10.30968/rbfhss.2017.083.005...
). Additionally, there is the IV drugs dilution manual and illustrative (in)compatibility guidelines with most frequently used agents at the nursing post, which can be consulted at the moment of scheduling and administration.

(In)compatibility evaluation represents one of the 13 rights of medication administration that, within ICU, indicate one of the main points for the complexity of the therapy. The existence of mistakes or negligence in the evaluation of this attribute will result in the violation of basic principles of professional responsibility(2828 Belela ASC, Peterlini MAS, Pedreira MLG. Erros de medicação: definições e estratégias de prevenção. Conselho Regional de Enfermagem de São Paulo e Rede Brasileira de Enfermagem e Segurança do Paciente - Polo São Paulo. [Internet]. São Paulo; 2011 [cited 2020 Feb 28]. Available from: https://www.passeidireto.com/arquivo/3881271/erros-de-medicacao-definicoes-e-estrategias-de-prevencao
https://www.passeidireto.com/arquivo/388...
). Consult manuals regarding IPM, double-checking the schedule (nurse and pharmacist), and use of millilumens devices are tools that may help in the prevention and reduction of IPM events(2222 Marsilio NR, Silva D, Bueno D. Drug incompatibilities in the adult intensive care unit of a university hospital. Rev Bras Ter Intensiva. 2016;28(2):147-53. https://doi:10.5935/0103-507X.20160029
https://doi:10.5935/0103-507X.20160029...
,2929 Vijayakumar A, Sharon EV, Teena J, Nobil S, Nazeer I. A clinical study on drug-related problems associated with intravenous drug administration. J Basic Clin Pharm. 2014;5(2):49-53. https://doi.org/10.4103/0976-0105.134984
https://doi.org/10.4103/0976-0105.134984...
).

In this study, although less than 10% of simultaneous infusions had been classified as incompatible, the potential adverse impact needs to be considered, especially because half of them could have precipitate formation as a consequence. Precipitate phenomenon is due mainly because the cations and anions combination existing in the solutions, which results in the formation of insoluble solids (precipitate)(3030 Newton DW. Drug incompatibility chemistry. Am J Health Syst Pharm. 2009;66(4):348-57. https://doi.org/10.2146/ajhp080059
https://doi.org/10.2146/ajhp080059...
). Thus, precipitate solutions often present microparticles and these may be responsible for the obstruction of venous devices(55 Kanji S, Lam J, Goddard R, Johanson C, Singh A, Petrin L, et al. Inappropriate medication administration practices in Canadian Adult ICUs: a multicenter, cross-sectional observational study. Ann Pharmacother. 2013;47(5):637-43. https://doi.org/10.1345/aph.1R414
https://doi.org/10.1345/aph.1R414...
,77 Benlabed M, Perez M, Gaudy R, Genay S, Lannoy D, Barthélémy C, et al. Clinical implications of intravenous drug incompatibilities in critically ill patients. Anaesth Crit Care Pain Med. 2019;38(2):173-80. https://doi.org/10.1016/j.accpm.2018.04.003
https://doi.org/10.1016/j.accpm.2018.04....
). A study performed with hemodialysis catheters showed that the composition of the occlusive material included crystalline drug precipitate incorporated in matrices formed by fibrin and blood cells(3131 Prasad GS, Ledger R, Puntis JWL, Ball PA. Occluding material present in central venous and haemodialysis catheters. BAPN Abstracts. Proc Nutr Soc. 1998;52-7.). Particles derivate from IPM may also irritate venous capillaries and contribute to the formation of microthrombi(3232 Hill SE, Heldman LS, Goo ED, Whippo PE, Perkinson JC. Fatal microvascular pulmonary emboli from precipitation of a total nutrient admixture solution. JPEN J Parenter Enteral Nutr. 1996;20(1):81-7. https://doi.org/10.1177/014860719602000181
https://doi.org/10.1177/0148607196020001...
). Cases of embolism were attributed to the precipitate of medications(3333 Ott MC, Khoor A, Scolapio JS, Leventhal JP. Pulmonary microcrystalline cellulose deposition from intravenous injection of oral medication in a patient receiving parenteral nutrition. JPEN J Parenter Enteral Nutr. 2003;27(1):91-2. https://doi.org/10.1177/014860710302700191
https://doi.org/10.1177/0148607103027001...
-3434 Buiter HJ, Blaauwgeers JLG, Van der Spoel JI, Franssen EJ. Erythromycin precipitation in vena femoralis: investigation of crystals found in postmortem material of an intensive care unit patient. Ther Drug Monit. 2008;30(1):125-9. https://doi.org/10.1097/FTD.0b013e31815bf864
https://doi.org/10.1097/FTD.0b013e31815b...
). Although it is difficult to establish the causal relationship between IPM and negative clinical outcomes that can cause irreversible damage to the patient, coadministration of incompatible drugs must be avoided.

Corroborating previous studies, the difference of pH of the coadministrated substances represented one of the main probable reasons for the occurrence of IPM(1414 Paes GO, Moreira SO, Moreira MB, Martins TG. Drug incompatibility in the ICU: review of implications in nursing practice. Rev Eletrôn Enferm. 2017;19:a20 https://doi.org/10.5216/ree.v19.38718
https://doi.org/10.5216/ree.v19.38718...
,2828 Belela ASC, Peterlini MAS, Pedreira MLG. Erros de medicação: definições e estratégias de prevenção. Conselho Regional de Enfermagem de São Paulo e Rede Brasileira de Enfermagem e Segurança do Paciente - Polo São Paulo. [Internet]. São Paulo; 2011 [cited 2020 Feb 28]. Available from: https://www.passeidireto.com/arquivo/3881271/erros-de-medicacao-definicoes-e-estrategias-de-prevencao
https://www.passeidireto.com/arquivo/388...
,3535 Nemec K, Kopelent-Frank H, Greif R. Standardization of infusion solutions to reduce the risk of incompatibility. Am J Health Syst Pharm. 2008;65(17):1648-54. https:// doi.org/10.2146/ajhp070471
https:// doi.org/10.2146/ajhp070471...
). The anticonvulsant phenytoin was the agent most often involved in combinations capable of causing precipitate formation. Highly alkaline pH (pH 12) and the low solubility of the medication make the mixture of this drug with other agents almost prohibitive(1111 Moraes CG, Silva D, Bueno D. Análise de incompatibilidades de medicamentos intravenosos no Centro de Tratamento Intensivo adulto do Hospital das Clínicas de Porto Alegre. Rev HCPA [Internet]. 2011[ cited 2020 Feb 27];31(1):31-8. Available from: https://seer.ufrgs.br/hcpa/article/view/14733/11591 Portuguese.
https://seer.ufrgs.br/hcpa/article/view/...
). However, weak acids, such as fentanyl, dobutamine, dopamine, midazolam, haloperidol, ondansetron and piperacillin + tazobactam, were simultaneously scheduled.

Incompatible pairs that included catecholamines (norepinephrine, dopamine and dobutamine), amiodarone, fentanyl, midazolam and propofol have been previously described(55 Kanji S, Lam J, Goddard R, Johanson C, Singh A, Petrin L, et al. Inappropriate medication administration practices in Canadian Adult ICUs: a multicenter, cross-sectional observational study. Ann Pharmacother. 2013;47(5):637-43. https://doi.org/10.1345/aph.1R414
https://doi.org/10.1345/aph.1R414...
-66 Kanji S, Goddard R, Donnely R, McIntyre L, Turgeon A, Coons P, et al. Physical compatibility of drug infusions used in Canadian Intensive Care Units: a program of research. Crit Care Med. 2010;38(9):1890-8. https://doi.org/10.1097/CCM.0b013e3181e8adcc
https://doi.org/10.1097/CCM.0b013e3181e8...
,1111 Moraes CG, Silva D, Bueno D. Análise de incompatibilidades de medicamentos intravenosos no Centro de Tratamento Intensivo adulto do Hospital das Clínicas de Porto Alegre. Rev HCPA [Internet]. 2011[ cited 2020 Feb 27];31(1):31-8. Available from: https://seer.ufrgs.br/hcpa/article/view/14733/11591 Portuguese.
https://seer.ufrgs.br/hcpa/article/view/...
-1212 Machotka O, Manak J, Kubena A, Vlcek J. Incidence of intravenous drug incompatibilities in intensive care units. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159(4):652-6. https://doi:10.5507/bp.2014.057
https://doi:10.5507/bp.2014.057...
). Norepinephrine (acid pH) was coadministrated mainly with sodium bicarbonate, an alkalinizing electrolyte solution that can lead to the chemical decomposition of the vasopressor due to the alkaline pH(1919 MICROMEDEX Healthcare Series [Internet]. New York; [2021]. Available from: https://www.ibm.com/br-pt/watson-health/about/micromedex [cited 2021 Mar 11].
https://www.ibm.com/br-pt/watson-health/...
). The pair midazolam × omeprazole (23.9%), very common in this cohort and reported in the literature(1111 Moraes CG, Silva D, Bueno D. Análise de incompatibilidades de medicamentos intravenosos no Centro de Tratamento Intensivo adulto do Hospital das Clínicas de Porto Alegre. Rev HCPA [Internet]. 2011[ cited 2020 Feb 27];31(1):31-8. Available from: https://seer.ufrgs.br/hcpa/article/view/14733/11591 Portuguese.
https://seer.ufrgs.br/hcpa/article/view/...
,1313 Silva LD, Matos GC, Barreto BG, Albuquerque DC. Drug scheduling for nurses in prescriptions at sentinela hospital. Texto Contexto Enferm. 2013;22(3):722-30. https://doi: 10.1590/S0104-07072013000300019.
https://doi:...
-1414 Paes GO, Moreira SO, Moreira MB, Martins TG. Drug incompatibility in the ICU: review of implications in nursing practice. Rev Eletrôn Enferm. 2017;19:a20 https://doi.org/10.5216/ree.v19.38718
https://doi.org/10.5216/ree.v19.38718...
,2222 Marsilio NR, Silva D, Bueno D. Drug incompatibilities in the adult intensive care unit of a university hospital. Rev Bras Ter Intensiva. 2016;28(2):147-53. https://doi:10.5935/0103-507X.20160029
https://doi:10.5935/0103-507X.20160029...
), can also cause PMI. These findings reinforce the importance of the team’s knowledge about the pH of medicines and IV solutions.

pH is considered one of the main factors used to maintain the stability of medicines. However, it is able to increase or decrease the speed of chemical reactions evolved in the degradation, especially when the optimum pH range of the drug is changed in mixtures (for upper or lower limits)(3030 Newton DW. Drug incompatibility chemistry. Am J Health Syst Pharm. 2009;66(4):348-57. https://doi.org/10.2146/ajhp080059
https://doi.org/10.2146/ajhp080059...
,3636 Trissel LA. Drug stability and compatibility issues in drug delivery. Cancer Bull.1990;42:393-8.). Loss of drug stability or degradation, even if identified only through laboratory investigations, is plausible to occur with some aforementioned combinations and may cause ineffectiveness of the drug, reiterating the relevance of the findings in this cohort.

Studies regarding medication (in)compatibility or specific combinations existing in therapeutic regimens used in the clinical context are limited, an aspect that reflects the lack of information on many mixtures, mainly in the national scenario(55 Kanji S, Lam J, Goddard R, Johanson C, Singh A, Petrin L, et al. Inappropriate medication administration practices in Canadian Adult ICUs: a multicenter, cross-sectional observational study. Ann Pharmacother. 2013;47(5):637-43. https://doi.org/10.1345/aph.1R414
https://doi.org/10.1345/aph.1R414...
-66 Kanji S, Goddard R, Donnely R, McIntyre L, Turgeon A, Coons P, et al. Physical compatibility of drug infusions used in Canadian Intensive Care Units: a program of research. Crit Care Med. 2010;38(9):1890-8. https://doi.org/10.1097/CCM.0b013e3181e8adcc
https://doi.org/10.1097/CCM.0b013e3181e8...
,1111 Moraes CG, Silva D, Bueno D. Análise de incompatibilidades de medicamentos intravenosos no Centro de Tratamento Intensivo adulto do Hospital das Clínicas de Porto Alegre. Rev HCPA [Internet]. 2011[ cited 2020 Feb 27];31(1):31-8. Available from: https://seer.ufrgs.br/hcpa/article/view/14733/11591 Portuguese.
https://seer.ufrgs.br/hcpa/article/view/...
,3737 Kanji S, Lam J, Johanson C, Singh A, Goddard R, Fairbairn J, et al. Systematic review of physical and chemical compatibility of commonly used medications administered by continuous infusion in intensive care units. Crit Care Med. 2010;38(9):1890-8. https://doi.org/10.1097/CCM.0b013e3181e8adcc
https://doi.org/10.1097/CCM.0b013e3181e8...

38 Mendes JR, Lopes MCBT, Vancini-Campanharo CR, Okuno MFP, Batista REA. Types and frequency of errors in the preparation and administration of drugs. Einstein (São Paulo). 2018;16(3):eAO4146. https://doi.org/10.1590/S1679-45082018AO4146
https://doi.org/10.1590/S1679-45082018AO...
-3939 Leal KDB, Leopoldino RWD, Martins RR, Veríssimo LM. Potential intravenous drug incompatibilities in a pediatric unit. Einstein (São Paulo). 2016;14(2):185-9. https://doi.org/10.1590/S1679-45082016AO3723
https://doi.org/10.1590/S1679-45082016AO...
). Injectable dipyrone is marketed in Brazil for decades, however, information regarding compatibility remains unknown. Furthermore, product instructions and international incompatibility screening systems do not contain data. This aspect that seems irrelevant to manufacturers, may compromise the safety of the patient. IPM risk during coadministration with other drugs may be real, even if unknown, mainly because it is a widely prescribed painkiller(3939 Leal KDB, Leopoldino RWD, Martins RR, Veríssimo LM. Potential intravenous drug incompatibilities in a pediatric unit. Einstein (São Paulo). 2016;14(2):185-9. https://doi.org/10.1590/S1679-45082016AO3723
https://doi.org/10.1590/S1679-45082016AO...
).

Study limitations

Although this study reveals valuable information to help to explain practices related to nursing team, within the scope of intravenous therapy, there were limitations that can be overcome in future investigations. The cohort was not designed to evaluate the clinic impact of IPM, such as occlusion or loss of catheters, precipitate formation or degradation of drugs. Despite the nature of retrospective of data, which avoided the identification of the contact time between medications, concentration of solutions, type of diluent, product manufacturers, drug preparation conditions, aspects that interfere with IPM, the findings reflect the practice of a university hospital.

Contributions for the Area

The double drugs identified integrate therapeutic regimes used in the current daily life of Brazilian critical units. The scheduling dynamics by the nursing team represents a challenge, not only due to the number of medications, but also due to the limitation of safe information on the topic.

The addition of the findings of the present study, despite not providing a broad overview of the problem, may contribute to the elucidation of the phenomenon in these units.

CONCLUSIONS

The organized work between the nursing team and the clinical pharmacist in the discussions and decisions about the scheduling certainly contributed to the greater occurrence of compatible mixtures in this cohort. Despite this, incompatible combinations (8.8%) predominantly occurred with medications that have extreme pH (4.5 ≤ pH ≥ 12), infused continuously and that integrate therapeutic regimes commonly used in critical units, which aspects illustrate the complex polypharmacy, the limitation of venous accesses, the risk of medications precipitate and, perhaps, the difficulty of the multidisciplinary team to apply the principles of good practices regarding IPMs in this context of critical care.

  • FUNDING
    To Research Support Foundation of the State of São Paulo – FAPESP, for funding the Project “Patient Safety in intensive and semi-intensive care units: the influence of human nursing factors on the occurrence of adverse events”, in which this survey is insert.

ACKNOWLEDGEMENT

To Ricardo Luis Barbosa for making the entire database of the aforementioned research.

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Edited by

EDITOR IN CHIEF: Dulce Barbosa
ASSOCIATE EDITOR: Mitzy Reichembach

Publication Dates

  • Publication in this collection
    28 May 2021
  • Date of issue
    2021

History

  • Received
    16 July 2020
  • Accepted
    01 Nov 2020
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