Hydrogen potential of antibiotic solutions subjected to environmental conditions: a preliminary trial

Abstracts

Estudo experimental para aferição do potencial hidrogeniônico (pH) dos antimicrobianos ceftriaxona sódica, cloridrato de vancomicina, metronidazol, penicilina G potássica e sulfato de amicacina, após reconstituição, diluição com NaCl 0,9% (SF) e soro glicosado 5% (SG), em oito momentos distintos e sob condições cotidianas de luminosidade e temperatura ambiente de unidade hospitalar não climatizada. O objetivo deste estudo foi verificar alterações no comportamento ácido-básico das soluções, indicativas de instabilidade química ou relacionadas a complicações da terapia intravenosa. Nos 186 valores de pH analisados, não foram identificadas variações maiores que 1,0 valor nem alterações físicas visíveis a olho nu. Todas as soluções tiveram pH menor que 7 e não houve diferença considerável para a prática clínica segundo o diluente. As médias dos valores de pH após a diluição em SF e SG, do cloridrato de vancomicina, metronidazol e sulfato de amicacina constituem fator de risco para o desenvolvimento de complicações intravenosas devido a sua extrema acidez.

Concentração de Íons de Hidrogênio; Estabilidade de medicamentos; Infusões intravenosas; Erros de medicação; Enfermagem pediátrica

ARTIGO ORIGINAL

Hydrogen potential of antibiotic solutions subjected to environmental conditions: a preliminary trial

Potencial de hidrógeno de soluciones de antibióticos sometidas a condiciones ambientales: ensayo preliminar

Cintia Monteiro^I; Renata Maria Coelho Crepaldi^II; Ariane Ferreira Machado Avelar^III; Maria Angélica Sorgini Peterlini^IV; Mavilde Da Luz Gonçalves Pedreira^V

^INursing Undergraduate, Federal University of São Paulo. CNPq fellow. São Paulo, SP, Brazil. [e-mail]

^IIRN, Graduated by the Federal University of São Paulo. São Paulo, SP, Brazil. [e-mail]

^IIIAdjunct Professor of the Pediatric Nursing Course, Paulista School of Nursing, Federal University of São Paulo. São Paulo, SP, Brazil. [e-mail]

^IVAdjunct Professor of the Pediatric Nursing Course, Paulista School of Nursing, Federal University of São Paulo. São Paulo, SP, Brazil. [e-mail]

^VAssociate Professor of the Pediatric Nursing Course, Paulista School of Nursing, Federal University of São Paulo. São Paulo, SP, Brazil. CNPq fellow. São Paulo, SP, Brazil. [e-mail]

Correspondence addressed

ABSTRACT

This experimental study was performed to assess the hydrogen potential (pH) of the antimicrobials ceftriaxone sodium, vancomycin hydrochloride, metronidazole, penicillin G potassium, and amikacin sulphate, following reconstitution, diluted with NaCl 0.9% (SF) and glucose solution 5% (GS), at eight different time intervals and under the normal daily conditions of lighting and temperature within the hospital unit (no air conditioning). The objective of this study was to verify the changes in the acid-base behavior of the solutions, which indicate chemical instability and can be associated with complications during intravenous therapy. Of the 186 analyzed pH values, there were no variations greater than 1.0 and no physical alterations visible to the naked eye. All solutions had a pH less than 7, and there were no significant differences for clinical practice regarding the diluent. The mean pH values after dilution with SF and GS for vancomycin hydrochloride, metronidazole, and amikacin sulphate are a risk factor for the development of intravenous complications due to their extreme acidity.

Descriptors: Hidrogen-Ion concentration; Drug stability; Infusions, intravenous; Medication errors; Pediatric nursing

RESUMEN

Estudio experimental de contraste del potencial de hidrógeno (pH) de antimicrobianos ceftriaxona sódica, clorhidrato de vancomicina, metronidazol, penicilina G potásica y sulfato de amikacina, luego de reconstitución, dilución con NaCl 0,9% (SF) y suero glucosado 5% (SG), en ocho momentos distintos, bajo condiciones normales de luminosidad y temperatura de unidad hospitalaria no climatizada. Objetivó verificar alteraciones del comportamiento ácido-básico de las soluciones, indicativas de inestabilidades químicas o relacionadas a complicaciones de terapia intravenosa. En 186 pH analizados, no se identificaron variaciones mayores a 1,0 valor, ni alteraciones físicas a simple vista. Todas las soluciones tuvieron pH menor a 7, no hubo diferencia considerable para la práctica clínica según el diluyente. Los promedios de valor de pH luego de dilución en SF y SG para clorhidrato de vancomicina, metronidazol y sulfato de amikacina constituyen factor de riesgo para desarrollo de complicaciones intravenosas debido a su extrema acidez.

Descriptores: Concentración de Iones de Hidrógeno; Estabilidad de medicamentos; Infusiones intravenosas; Errores de medicación; Enfermería pediátrica

INTRODUCTION

Since 1860, Florence Nightingale emphasized the need for nurses to know the correct preparation, dosage, technique of administration, and expected and adverse effects of each medication. In the mid-1950s, the administration of intravenous (IV) drugs and solutions became the providence of nurses, used in patients who are incapable of ingesting the necessary quantity of fluids, electrolytes, vitamins and/or calories, in situations such as electrolyte imbalance, blood loss, dysfunction of several organs and systems, infection, surgical procedures and major burns, among others⁽¹⁾.

A study developed at a teaching hospital showed that the mean number of doses of drugs administrated intravenously in children was 6.8 per day. This result indicates the extent of use of this therapy in pediatric patients⁽²⁾. Among the drugs intravenously infused, antibiotics stand out, requiring specialized nursing care for their administration regarding dilution and the time of infusion⁽³⁾. Due to the lack of presentation of medications in the appropriate doses for this age range in the national market, reconstitution is frequently performed prior to their administration. However, questions arise as to the stability of these drugs following reconstitution regarding sterility, the presence of pyrogens and the time of storage prior to administration⁽²⁾.

The maintenance of the pharmacological stability and physical-chemical compatibility are critical elements in the correct and appropriate offer of drug therapy to the patient. The adaptation and safety of the therapy may be adversely affected by drug instability. There is a high potential for stability problems with the medication if there are long periods of contact and exposure to environmental conditions, such as temperature and light⁽⁴⁾.

Drug instability is defined as the occurrence of chemical reactions that result in molecular changes, creating different compounds than intended and resulting in a degraded product. The degraded product may be an inactive therapeutic substance or even a toxic substance produced in the reaction. The stability of a drug is considered to be the period for which it keeps 90% of its initial concentration, in its presentation, reconstitution or dilution. A stable drug solution presents molecules with electrospheres that repel themselves mutually. For the chemical reaction to occur, there must be the necessary quantity of energy to overcome this repulsion, promoting the approach of the molecules and the rupture of the bonds existing among the atoms of each substance, favoring the occurrence of other bonds and, consequently, the synthesis of a new compound. Therefore, in technical terms, it is possible to state that a chemical reaction occurs when the kinetic energy exceeds the activation energy; catalysts, being capable of lowering the activation energy, contribute to increase the speed of reaction^(4-7).

The main factors that may influence drug decomposition rate are the different hydrogen potentials (pH) of a solution, the temperature to which the drug is exposed, the concentration of the drug in the solution and the exposure to lighting⁽⁴⁾.

The pH is defined as the concentration of hydrogen ions present in a solution, being classified as neutral when similar to the negative logarithm (10^-7), since it allows hydrogen ions to be neutralized by hydroxyl ions⁽⁸⁾.

Several drugs are sufficiently stable in the pH scale between 4 and 8 if administrated in a specified period of time, being less detrimental to the vascular endothelium, even in peripheral veins of small caliber. Those formulated in more acidic pH values (under 4), have a higher lifetime of drug administration and this characteristic is identified in several antibiotics, which leads to a risk of developing complications at the intravenous therapy site. It is important to highlight that the association (mixture) of drugs with different pH values may lead to a change in one of the components in the solution mixture, generating drug instability and increasing the risk of incompatibility⁽⁴⁾.

Considering that the substances most frequently used as diluents for intravenous infusion of drugs and electrolytes are sodium chloride 0.9% in water (SF), which presents a mean value of pH of 6.33, and glucose 5% in water (GS), with a mean pH of 6.24, and that these values were measured during the development of this study, it would be interesting to study the acid-base behavior of drugs diluted in these solutions, since solutions administrated intravenously should not present extreme pH values, in order to avoid intravenous therapy complications, such as phlebitis and infiltration⁽⁹⁾_.

Phlebitis may be classified as chemical, mechanical or infectious. High osmolar concentration and pH extremes of the solution are the main factors in the development of chemical phlebitis, triggering an inflammatory process in the tunica intima of the vein. Infiltration is defined as the accidental administration of non-vesicant drugs or solutions into the extravascular space, with the possibility of being secondary to the occurrence of phlebitis. The composition and dosage of the medication, inappropriate reconstitution and dilution, mixture of incompatible drugs and fast infusion rates, in addition to other factors, may result in phlebitis and infiltration^(9-11).

This study aims at analyzing the pH values, at different periods of infusion, of five antibiotics frequently used in a pediatric surgical unit where there was no air conditioning system, at a teaching hospital in the city of São Paulo, supposing that the factors dilution and time of exposure to environmental conditions result in pH values of antibiotics for IV administration different from those identified in controlled environmental conditions, so as to obtain evidence of clinical relevance for nursing professionals in the execution of IV therapy.

OBJECTIVES

Assess the hydrogen potential (pH) of antibiotics, at different periods following their reconstitution and dilution for IV administration in children, and exposed to environmental conditions in a pediatric surgical unit; compare the obtained pH values to those found in controlled laboratory situations; and identify antimicrobials with pH values that could constitute a risk factor for complications at IV therapy sites.

METHOD

After obtaining approval from the Committee of Ethics in Research (no. 1458/06), an experimental study was developed regarding the pH of antibiotics immediately following their reconstitution and dilution and at different periods of time that simulate the infusion techniques employed in nursing clinical practice.

The sample comprised 186 pH values of five antimicrobials, which are among the most frequently used antibiotics in the hospital unit in which this study was developed: ceftriaxone sodium, vancomycin hydrochloride, metronidazole, penicillin G potassium and amikacin sulphate.

Experiments were performed at three different times, distributed on days I, II and III, according to the randomization of the morning and evening shifts.

The preparation of the antimicrobials and the assessment of the pH immediately following reconstitution were performed in the room where the medications are prepared. The exposure of the drug solutions for IV infusion to environmental conditions and the pH assessment were performed within a children's hospital room. Both exposure areas were lit up with fluorescent lamps, and this experiment was performed in a hospital environment characterized as experiment 1 (E1).

The final pH values were assessed by a previous study developed in a laboratory with the same antimicrobials and denominated experiment 2 (E2), in an environment without the influence of lighting and provided with air conditioning in order to obtain a temperature of 22ºC, as well as materials and equipment that would characterize the appropriate condition for the maintenance of the drug stability, were used as reference values to compare the influence of the studied situations on the pH of the studied drugs⁽¹¹⁾. The same materials and techniques were employed in E1 and E2.

PH values were assessed at different periods of time : immediately after reconstitution in distilled water or solution in liquid presentation; 24 hours following reconstitution under refrigerated conditions; t0 – immediately after dilution; t1 – five minutes after dilution; t2 – 30 minutes after dilution; t3 – 60 minutes after dilution; t4 – 120 minutes after dilution; and t5 –24 hours after dilution.

The drugs were reconstituted with distilled water and diluted with SF or GS, according to the nursing protocols for the administration of antimicrobials at the studied teaching hospital. Following reconstitution, ceftriaxone sodium, vancomycin hydrochloride and penicillin G potassium yielded the following concentrations, respectively: 100mg/ml, 100mg/ml and 500,000 U/ml. Amikacin sulphate and metronidazole did not require reconstitution and were used in concentrations of 250mg/ml and 5mg/ml, respectively. However, the latter was not diluted since, according to the manufacturer's recommendations, it presents the ideal concentration for IV administration⁽¹²⁾.

In order to verify the pH after reconstitution, a sample was taken from the vial, the remaining portion was diluted and the rest of the sample remained in the vial to be refrigerated to allow later assessment of the pH of the solution after 24 hours of refrigeration.

The final concentration of each drug, after dilution, was 20mg/ml for ceftriaxone sodium; 5mg/ml for vancomycin hydrochloride, metronidazole and amikacin sulphate; and 50000U/ml for penicillin G potassium. The final volume of the solutions was established at 20 ml for all drugs, being diluted and stored in syringes of 20 ml volume.

In each period of assessment, a sample from the solution stored in syringe was removed to be conditioned in a glass beaker and to allow assessment via the digital pH meter ExStik^TM PH 100, manufactured by Extech® (EUA).

The luminous intensity of the environment, in lux (lx), was assessed with a portable digital lux meter (model LD-510), and temperature control was performed with two digital thermometers (model 7429, manufactured by TFA^® Dostmann, Reicholzhein, Baden-Württemberg, Germany). The temperature and luminosity were verified in the time periods t1, t3, t4, t5 and following 24 hours of refrigeration; however, in this last instance only the temperature was verified, because there is not constant luminosity inside a refrigerator.

PH values are presented in tables and figures and described statistically in maximum values (max), minimum values (min), mean and standard deviation (m±dp) for each studied situation. The inferential statistics were performed using Student's t-test between the pH means of the control and experiment groups, considering a significance level of 5%.

RESULTS

A total of 186 assessments of pH were performed, 42 (22.58%) for ceftriaxone sodium, 42 (22.58%) for vancomycin hydrochloride, 42 (22.58%) for penicillin G potassium, 39 (20.97%) for amikacin sulphate and 21 (11.29%) for metronidazole.

Both the temperature and the lighting presented great variation during the experiments, with a mean environmental temperature in the three days of experiments of 26.34ºC, varying from 19.10ºC to 33.30ºC, demonstrating the environmental condition of a hospital unit without air conditioner in a tropical country, representing higher values than recommended for the exposure of medications during administration (22ºC). The refrigerator in which the medications were stored presented a mean temperature of 7.30ºC, varying from 2.70ºC to 13ºC.

After reconstituting the antimicrobial or opening the vial, the less acidic drugs were ceftriaxone sodium and penicillin G potassium, and those presenting more acidic pH values were amikacin sulphate and vancomycin hydrochloride. Considering the experiments took place over three days, all antimicrobials presented a standard deviation less than 0.24, either higher or lower. The drug with the greatest variation was amikacin sulphate and the one with the least variation was metronidazole (Table 1).

It is observed that, even after storage for 24 hours, there was no significant change in the pH values of the antimicrobials, when compared to the mean values in the period following reconstitution (Table 1), highlighting that all of these drugs may be kept under refrigeration for this period of time, according to the manufacturer's recommendations.

As follows, Figure 1 presents a visual representation of the pH values of metronidazole and the drugs diluted in SF and exposed to different environmental conditions (E1 and E2).

In both experiments, ceftriaxone sodium and penicillin G potassium became more acidic after being diluted in SF, whereas the antimicrobials amikacin sulphate and vancomycin hydrochloride became less acidic (Figure 1).

Nevertheless, these last two drugs were the ones that resulted in lower pH values: vancomycin hydrochloride presented means 4.09±0.13 and 3.27±0.07, respectively in E1 and E2, and amikacin sulphate with mean values 4.83±0,20 and 5.01±0.03, respectively in E1 and E2 (Table 2).

In 24 hours of exposure, ceftriaxone sodium and vancomycin hydrochloride obtained higher pH values than in the other time intervals. Penicillin G potassium, however, became more acidic over time in E1 and less acidic in E2. Amikacin sulphate maintained its acid-base behavior without significant changes during the experiment, while vancomycin hydrochloride presented a tendency to increase in pH value over time in both experiments. Metronidazole presented small pH variations, following a stable curve throughout the entire time of exposure, except in the 24 hour interval in E2 (Figure 1).

Table 2 shows that in the dilution with SF, the drugs with the highest variability in pH values in E1 were amikacin sulphate (4.83±0.20) and penicillin G potassium (6.34±0.20). In E2, the antimicrobial with the greatest variability after the use of the same diluent was ceftriaxone sodium (6.32±0.28). However, all the solutions of antimicrobials diluted in SF presented variation of less than 1.0 pH value over time in the two experiments.

In comparing the experiments, it is observed that metronidazole, a drug that is manufactured in liquid presentation and in the ideal concentration for IV administration, presented the highest changes in pH value (5.47±0.34) throughout the time of exposure in E2 (Table 2).

Except for ceftriaxone sodium, all drugs diluted in SF presented a significant difference between the mean pH values when comparing the two experiments (Table 2). >It is important to highlight that the medication vials used in E1 and E2 were not the same; in other words, the factor responsible for the generation of different pH values over time may have been a different initial pH for each vial, rather than the environmental conditions, although it was initially expected that medications from the same manufacturer submitted to the same analysis procedure would not present the identified variations.

Of the drugs diluted in GS, vancomycin hydrochloride was the most acidic antimicrobial over time, with a mean of 3.96+0.08 in E1 and 3.39+0.15 in E2. On the other hand, the least acidic antimicrobial was penicillin G potassium with a mean of 6.60+0.15 in E1 and 6.64+0.12 in E2 (Table 2).

Figure 2 presents the acid-base behavior of the antimicrobials diluted in GS. It is possible to observe that even after dilution in GS, ceftriaxone sodium and (mainly) penicillin G potassium presented decreased pH values, whereas vancomycin hydrochloride and amikacin sulphate resulted in increased pH values following dilution (Figure 2).

It is possible to observe through Figure 2 that, in both experiments, amikacin sulphate presented a small pH variation over time. Vancomycin hydrochloride was stable in E1, but in E2 showed an increased pH in t3 and a decrease thereafter. Penicillin G potassium, despite being rather stable over time, presented a decrease in pH in the last 24 hours of exposure in E1 and in E2. Regarding ceftriaxone, it is observed that, despite presenting a stable behavior over time in E1 with an increase of pH in the 24 hours of exposure, in E2 there was acidification until t2; after that the pH value increased, reaching its maximum value in t5.

All solutions of antimicrobials diluted in GS presented a variation in pH of less than 1.0 over time in the two experiments.

Except for penicillin G potassium, all drugs diluted in GS presented different pH values in the two experiments (Table 2). Similar to what happened in the experiments in which the medications were diluted in SF, the difference between the means was identified in the initial values, evidencing different pH values in different vials of a same drug of a certain manufacturer.

Comparing the results for the diluents, it is observed that vancomycin hydrochloride tends to become more acidic when diluted with GS. On the other hand, ceftriaxone sodium, penicillin G potassium and amikacin sulphate had a more acidic behavior with SF as the diluent. In E2, all drugs were more acidic when diluted with SF (Table 2).

DISCUSSION

The intravenous administration of drugs and solutions in children constitutes a challenge for evidence-based nursing practice for the promotion of safe interventions, due to the lack of drugs specifically presented for this age range, studies regarding this subject or support from the pharmaceutical industry that allow nurses to analyze the scientific adaptation of normal daily activities performed in routine care practice. Therefore, it is important for the nursing professionals to study the foundations that support their practice in the administration of drug therapy, promoting the advance of science and the nursing interventions provided to the patient.

In light of the problem of drugs not being manufactured for the pediatric age range, professionals must reconstitute antimicrobials, store them in refrigerators and later perform the dilution in volumes and solutions for IV infusion, administering them at later periods of time to avoid deleterious adverse factors in the children⁽²⁾. For these reasons, several drugs conditioned in vials are reused in health services, therefore avoiding the waste of antimicrobials that are costly, assisting in the control of expenses in the institution. Nevertheless, this reuse may compromise the quality and safety of the IV therapeutics⁽¹³⁾.

In this context, questions emerge regarding the possible alterations in the chemical behavior of the solutions following their refrigeration and dilution, and regarding the action of catalysts such as temperature and lighting for long periods of infusion in environmental conditions of hospital units without air conditioning systems.

The temperature, both in vitro and in vivo, is directly related in proportion to the quantity of random vibratory movements of the atoms that compose the molecules of a certain solution, having the capability of influencing the speed of chemical reactions by promoting a kinetic energy higher than the activation energy. In general terms, for each increase of 10ºC in a solution, the speed of the reaction may double and even quadruple⁽¹⁴⁾.

The storage of vials in refrigerators requires the temperature to remain constant between 4ºC and 8ºC in order to maintain drug stability⁽¹⁵⁾. In the present study the minimum temperature of the refrigerator was 2.7ºC and the maximum was 13ºC. This variation could not maintain the desired temperature of the used drugs, but the frequent opening of the refrigerator prevents the temperature from remaining at safer levels. As for the pH variations, this situation did not cause a significant influence; however, it does not allow us to analyze other aspects regarding the therapeutic quality of the studied solutions. Nursing, by assuming the responsibility for the storage and administration of medications in hospital units, must take responsibility for safe practices.

The increase of the environmental temperature influences the degradation of the solutions, changing the pH and consequently leading to instability of the drug. Penicillin G potassium and cephalosporins are described in the literature as vulnerable to heat⁽⁴⁾. Penicillin G potassium diluted in SF presented the highest standard deviation (0.20), which evidences a more variable characteristic of this drug.

An experiment⁽¹⁶⁾ showed that this antimicrobial, in the concentration of 5000U/mL, presented minimum pH variation at temperatures of 4ºC, 25ºC and 37ºC, in SF (5.89 to 6.19) and GS (4.82 to 6.39). According to the present study, penicillin G potassium diluted in SF presented a pH mean 6.34 and in GS 6.60, allowing us to observe that it presented a higher mean value in both diluents when compared to the study previously mentioned. In E2, when diluted in SF, this drug presented very similar values to those found in E1, mainly with GS used as the diluent. It is important to highlight that the concentration of penicillin, in Wyatt's study, was ten times lower than the concentration obtained with the same antimicrobial in E1 and E2.

Furthermore, it is possible to verify through the literature that penicillin G potassium is stable for a period of less than 24 hours⁽¹⁷⁾. In this study, the drug presented a small variation in the pH values until 24 hours after exposure to environmental conditions.

An experimental study identified that ceftriaxone sodium in distilled water (100mg/mL) and stored in polypropylene syringes remained stable for 40 days at a temperature of 4ºC, and for five days at 20ºC, with changes in the color of the solution. This was associated with a minimum change in the pH value (7.07 to 7.13) between 24 and 120 hours⁽¹⁸⁾. PH values were higher than those found in this study due to the difference of concentration of the solutions and to the diluents used, which are more acidic than distilled water, constituting a risk factor for the occurrence of complications.

By comparing the values obtained in E1 and E2, it is observed that ceftriaxone sodium presented a higher variation when exposed to the environmental condition of 22ºC without lighting, regardless of the diluent used, which contradicts the information that this drug is vulnerable to heat. Ceftriaxone sodium did not present significant variations, as diluted in SF it presented a mean pH of 6.38(±0.17) and in GS 6.49 (±0.11).

Regarding luminosity, it is known that it activates reactions of photodegradation, such as oxidation and hydrolysis. Thus, the more intense a source of light is and/or the closer the photosensitive drug is to this source, the higher the degradation degree and rate ⁽⁴⁾. The light, containing electromagnetic radiation, propagates in space transporting energy that may, through photolysis, decompose a molecule through the unfolding or readjustment of its chemical bindings. The wave length is inversely proportional to its energy; thus, the photodegradation of the drug increases, respectively, in the following lighting situations: incandescent, fluorescent, sun and ultraviolet rays⁽¹⁴⁾.

Metronidazole is described as being a drug sensitive to lighting during storage and administration. However, in clinical practice, during IV administration of this drug, protection from environmental light is not a concern⁽¹²⁾. The experiments performed in the present study show that there were no significant changes in the pH value of this drug, which presented a lower standard deviation (0.03) in comparison to the other studied drugs, with a mean pH of 4.97, despite being administrated in a unit without air conditioning and without the use of infusion systems with photoprotection.

Therefore, it is observed that even when exposed to environmental conditions with natural lighting, it maintained its acidic and stable behavior (E1).

Regarding complications of IV therapy, a national clinical study performed with children showed that 4.7% of the peripheral IV catheters were removed due to phlebitis and 55.3% due to infiltration⁽¹⁹⁾. The significant irritation of the endothelium, caused by the chemical composition of the solution (pH or osmolar concentration), may damage the intima layer of the vein and predispose to the occurrence of phlebitis, with the possibility of a secondarily occurring infiltration⁽¹⁰⁾.

The risk range for complications of IV therapy corresponds to pH values below 5.5 and above 8.0⁽⁹⁾. Antibiotic therapy increases the risk of development of phlebitis⁽²⁰⁾, mainly due to the time of exposure of the endothelium to this substance. The study found that the incidence of this complication related to the administration of antibiotics was 18.5%, whereas without the use of this drug it was 8.8 %⁽²¹⁾. This result may be related to the acidic nature of these drugs.

Cephalosporins, penicillin and vancomycin are considered to be irritating antimicrobials to the vascular endothelium⁽²²⁾. In addition, solutions reconstituted using glucose increase the risk of phlebitis occurring, in comparison to SF⁽²⁰⁾. In the present study, it is observed that vancomycin hydrochloride, amikacin sulphate (regardless the diluent used) and metronidazole constitute a risk factor for the development of local complications of IV therapy.

Some medications are unstable in acid (pH < 4) or alkaline solutions (pH > 8) and among these drugs, some antimicrobials stand out ⁽⁷⁾. For this reason, it is extremely important to analyze the pH of the components in solution, in order to avoid therapeutic harm and/ or complications ⁽⁴⁾.

In this study, the only antimicrobial that presented extremes in pH values was vancomycin hydrochloride diluted in SF (3.95 to 4.39) and GS (3.76 to 4.10). By comparing these data to those obtained in E2, it was verified that the values were even lower (3.16 to 3.38 in SF and 3.27 to 3.65 in GS).

It is possible to observe that, when comparing both experiments (E1 and E2), the antimicrobials that presented statistically significant variations were vancomycin hydrochloride, penicillin G potassium and amikacin sulphate, diluted in SF, and ceftriaxone sodium, vancomycin hydrochloride and amikacin sulphate, diluted in GS. Therefore, the antibiotics that presented significant changes are not the same for both diluents. It is possible to infer that there may be a difference between the means because the vials of medications used in E1 were not the same as those used in E2; that is, the different initial pH of each vial, instead of the environmental conditions, is what may have led to different pH values over time.

This finding is relevant because it highlights unexpected differences between medications from the same manufacturer. It is important to note that a great many of the medications used in this study are classified as off-label and generic drugs.

Through this study, it is observed that all antimicrobials presented pH variations of less than 1.0 throughout the time of exposure to the environmental conditions. If such a variable is capable of changing the pharmacological properties of the studied substances, it requires further investigation using other methodologies for drug stability analysis, such as HPLC - High Performance Liquid Chromatography. This methodology employs a physical-chemical method that separates liquids of a mixture into their individual components, identifying and quantifying the final products of the mixture and registering these data in a chromatogram⁽¹⁴⁾.

Among the study limitations, it is important to highlight that it is not possible to determine possible changes in the therapeutic properties of the drugs through only the pH assessment, especially given the fact that in E2 the pH assessments were performed only once in each experiment. Moreover, pH means obtained in E1 and E2 from different vials, and whose initial values were already different were compared, which may have compromised the final results.

Nevertheless, the results obtained show the need to rethink clinical practices and to develop collaborative studies between nursing and pharmacology aimed at promoting nursing practices based on scientific evidence. The use of medication in their clinical practice requires nurses' reflection regarding the need to perform a critical analysis of the support provided by the industry for the safe administration of IV medications. It is also observed that, even after the application of the dilution protocol routinely used for the infusion of antimicrobials in children, the pH remains close to that obtained in the initial pharmacological presentation, increasing the risk for the development of complications of intravenous therapy such as phlebitis and infiltration, which are intended to be prevented with dilution of the drug, this fact being identified in all assessments, regardless the diluent used.

CONCLUSION

Inconsistent pH values were observed neither in the pharmacological presentation nor after reconstitution. Ceftriaxone sodium, penicillin G potassium and amikacin sulphate stood out as the antimicrobials that underwent the greatest variation in the pH value over time, regardless of the diluent used. There was no identification of pH variations higher than 1.0 or characterized changes in the behavior of the solutions from acid to basic, or vice-versa.

When compared to a similar study, it was observed that the drugs presenting pH values with statistically significant differences were vancomycin hydrochloride, penicillin G potassium and amikacin sulphate diluted in SF, and metronidazole. With the diluent GS, ceftriaxone sodium, vancomycin hydrochloride and amikacin sulphate were the antimicrobials that presented a significant difference.

Some of the pH values obtained constitute a risk factor for the development of local complications of IV therapy, especially vancomycin hydrochloride, amikacin sulphate and metronidazole, without relation to the diluent used.

This study indicates the need to broaden knowledge through the development of studies on this subject, providing the nurse with the scientific support to plan and implement care, resulting in more qualified and safer care, since the nurse is fundamental in the administration of drug therapy, particularly in children, who require specific care to assure the effectiveness of drug therapeutics.

REFERENCES

• 1. Kuhn M. Pharmacotherapeutics: a nursing process approach. 4th ed. Philadelphia: FA Davis; 1998.
• 2. Peterlini MAS, Chaud MN, Pedreira MLG. Órfãos de terapia medicamentosa: a administração de medicamentos por via intravenosa em crianças hospitalizadas. Rev Latino Am Enferm. 2003;11(1):88-95.
• 3. Pedreira MLG, Chaud MN. Terapia intravenosa em pediatria: subsídios para a prática de enfermagem. Acta Paul Enferm. 2004;17(2):222-8.
• 4. Trissel LA. Drug stability and compatibility issues in drug delivery. In: Trissel LA. Handbook of injectable drugs. 11th ed. Bethesda: American Society of Health-System Pharmacistis; 2001.
• 5. Reis LL, Peterlini MAS, Pedreira MLG. Potencial hidrogeniônico de soluções de cloridrato de dobutamina expostas a condições ambientais de unidades de cuidados intensivos neonatais. J Pediatr. 2009;85(6):553-6.
• 6. Stella VJ. Chemical and physical bases determinin the instability and incompatibility of formulated injectable drugs. J Parent Sci Technol. 1986;40(4):142-63.
• 7. Newton DW. Physicochemical determinants of incompatibility and instability in injectable drugs solutions and admixtures. Am J Hosp Pharm. 1978;35(10):1213-22.
• 8. Weinstein SM. Plumer's principles and practice of intravenous therapy. 6th ed. Philadelphia: Lippincott; 1997.
• 9. Phillips LD. Manual de terapia intravenosa. 2Ş ed. Porto Alegre: Artmed; 2001.
• 10. Pettit J. Assessment of an infant with a peripheral intravenous device. Adv Neonatal Care. 2003;5(5):230-40.
• 11. Crepaldi RMC, Monteiro C, Peterlini MAS, Pedreira MLG. Hydrogen-ion potential of antibiotics according to the environment factors temperature and luminosity. Rev Latino Am Enferm. 2010;18(2):278-86.
• 12. Micromedex^® Healthcare Series [Internet]. New York: Thomson Reuters; 2009 [cited 2009 Aug 23]. Available from: https://www.thomsonhc.com/hcs/librarian/CS/B466C4/PFActionId/pf.HomePage/ssl/true
• 13. Souza MCP, Goulart MA, Rosado V, Reis AMM. Utilização de medicamentos parenterais em frascos-ampola em uma unidade pediátrica de um hospital universitário. Rev Esc Enferm USP. 2008;42(4):715-22.
• 14. Reis LL. Potencial hidrogeniônico de soluções de cloridrato de dobutamina expostas a condições ambientais de unidades de cuidados intensivos neonatais [dissertação]. São Paulo: Universidade Federal de São Paulo; 2007.
• 15. Telles PCPF, Cassiani SHB. Administração de medicamentos: aquisição de conhecimentos e habilidades requeridas por um grupo de enfermeiros. Rev Latino Am Enferm. 2004;12(3):533-40.
• 16. Wyatt RG, Okamoto GA, Feigin RD. Stability of antibiotics in parenteral solutions. Pediatrics. 1972;49(1):22-9.
• 17. Gilbert DN, Dworkin RJ, Raber SR, Leggett JE. Outpatient parenteral antimicrobial-drug therapy. N Engl J Med. 1997;337(12):829-39.
• 18. Plumridge RJ, Rieck AM, Annus TP, Langton SR. Stability of ceftriaxone sodium in polypropylene syringes at -20, 4, and 20 degrees C. Am J Health Syst Pharm. 1996;53(19):2320-3.
• 19. Machado AF, Pedreira MLG, Chaud MN. Eventos adversos relacionados ao uso de cateteres intravenosos periféricos em crianças de acordo com tipos de curativos. Rev Latino Am Enferm. 2008;16(3):362-7.
• 20. Maki DG, Ringer M. Risk factors for infusion-related phlebitis with small peripheral venous catheters: a randomized controlled trial. Ann Intern Med. 1991;114(10):845-54.
• 21. Lanbeck P, Odenholt I, Paulsen O. Antibiotics differ in their tendency to cause infusion phlebitis: a prospective observational study. Scand J Infect Dis. 2002;34(7):512-9.
• 22. Turnidge J. Hazards of peripheral intravenous lines. Med J Aust. 1984;141(1):37-40.

Correspondência:

Ariane Ferreira Machado Avelar

Escola Paulista de Enfermagem, Universidade Federal de São Paulo

Rua Napoleão de Barros, 754 - Sala 113 - Vila Clementino

CEP 04024-002 - São Paulo, SP, Brasil

Publication Dates

• Publication in this collection
  07 May 2012
• Date of issue
  Apr 2012

History

• Received
  29 Sept 2010
• Accepted
  26 Aug 2011