With the aid of this guide, intravenous treatment practitioners will be able to better comprehend some of the challenges surrounding physico-chemical drug interactions that are pertinent to IV drug therapy and parenteral nutrition.
Some ideas are illustrated with the use of case studies, and practical recommendations are provided.
Incompatibilities Between Drugs in IV Drug Therapy
The administration of various IV medication regimens, as well as parenteral nourishment, to critically sick patients is not uncommon. This requires the use of a large number of peripheral and central infusion lines as well as accompanying equipment. However, owing to a shortage of venous access sites, certain drugs may be supplied together via a single lumen in order to save time and money. Because of the large variety of medications, IV solutions, and nutrients that are employed, there is a significant possibility for drug, carrier fluid, and nutritional interactions to develop.
A common misconception about drug interactions is that they are dangerous. When multiple medications are present in a patient’s systemic circulation, they can cause a variety of adverse effects, including: potentiation or antagonism of pharmacological effects, protein binding, altered/delayed/increased metabolism, and other side effects. Pharmacodynamic and pharmacokinetic interactions that have the potential to be hazardous or even deadly are widely understood, and precautions are made to prevent them wherever feasible. Despite this, there is the possibility for less well-known interactions to occur even before the medicine enters the patient’s system. Infusion system drug interactions may arise when one or more medications and IV fluids are combined together in the same container. These are known as physico-chemical drug interactions.
Factors affecting compatibility
The compatibility and stability of medications may be affected by a variety of variables, including changes in preservatives, buffering systems, delivery vehicles, temperature, concentration, and the sequence in which they are mixed. Because of changes in formulas, different brands of the same medicine may vary in their potential compatibility with other drugs.
Types of interactions
A variety of diverse responses may occur as a consequence of incompatibilities between various drugs, which can occur as a result of chemical or physical-chemical interactions. Oxidation, reduction, hydrolysis, decarboxylation, breakdown, esterisation and substitution reactions are some of the chemical processes that may occur between drugs. Other chemical reactions include polymerization and complex formation.
Inactive drug complexes or even whole new chemical entities may be formed as a consequence of these interactions, the toxicity of which will remain unknown. Apart from altering the pharmacology of drugs, the consequences of such interactions may also alter the solubility of one or more components, resulting in the creation of a precipitate containing an insoluble drug or complex.
It is possible to have a variety of physico-chemical interactions, ranging from association to sorption to consistency changes and precipitation to the separation of dispersion systems. These, too, may result in inactivation or altered toxicity, as well as unstable solution systems, as previously mentioned.
If a medication’s solubility profile is different from that of a second medication or solution, for example, if one medication is formulated to be stable at pH8 (basic conditions) and the other at pH4 (acidic conditions), and the two solutions are mixed, for example, through a Y-site or stopcock, the resulting change in pH may result in one or both of the medications becoming insoluble, leading to leadin.
However, in many cases, there may be no visible sign of incompatibility between two materials.
Patient phlebitis (inflammation of the peripheral veins) may result from the inadvertent administration of particles or a precipitate of incompatible medicines. Experiments in which IV filters were employed to remove particles from IV treatment have shown the relative significance of particulate material such as precipitates to the development of phlebitis. Five double-blind trials comparing filtered and non-filtered infusion treatment found that the incidence of phlebitis was at least reduced in the filtered group. End-line IV filters have been shown in a number of clinical trials to greatly minimize the prevalent issue of infusion-related phlebitis3, 11, which is a serious infection.
It is possible for particles or precipitates to reach the systemic circulation via either central or peripheral lines, posing a risk of life-threatening consequences. A large body of clinical literature has recorded the adverse effects of unintended particulate infusions on patients’ pulmonary circulation systems, and current research has revealed the dangers of micro-particle infusions on patients’ pulmonary circulation systems. A study by Dr Helen Walpot12 and another by Professor CJ. Kirkpatrick13,14 show that the deposition of particulate matter in the microvasculature of the lungs might contribute to the development of Acute Respiratory Distress Syndrome in patients in intensive care units (ICUs). In 1994, two patients died and at least two others showed respiratory distress after an unintentional calcium phosphate precipitation was infused into a peripheral parenteral nutrition admixture, which was described as a lethal consequence of precipitates15.
Because of their training, expertise, formulation knowledge, and access to information, hospital pharmacists are in the greatest position to provide advise on the safety and appropriateness of combining preparations. Several hospital pharmacists have central intravenous additive services (CIVAS) to help them make the most of their limited resources, and many of them also provide a parenteral nutrition admixture compounding service.
Several papers have been published in recent years that explore the compatibility of medications and carrier solutions. In drug makers’ data sheets or Summaries of Product Characteristics19, the compatibilities of formulations are often mentioned. Standard publications, such as Lawrence Trissel’s Handbook of Injectable Drugs20 or national formularies (for example, the British National Formulary21), are great sources of information on injectable drugs. These studies or books, on the other hand, are often limited to the compatibility of a single medicine with a carrier solution or another drug in general. There is limited understanding of compatibility issues with the complicated infusion regimens and systems that are often employed in critical care – a circumstance in which many drugs, in varying doses, may be supplied simultaneously via IV lines. When many infusions are required, flushing IV lines with appropriate carrier fluid between bolus medication doses may be beneficial in reducing the likelihood of drug interactions, although this is not a procedure that is always feasible with multiple infusions. We could not analyze all possible drug compatibility permutations due to the huge number of potential medications or solution combinations that might be used. This is due to the vast number of potential drugs or solution combinations that may be utilized. Recently conducted research has looked at these challenges and problems, and the findings have identified methods that may be performed to reduce the likelihood of these possible problems occurring.
Dr. Kuhl and colleagues from the Elisabeth hospital in Essen (Germany) examined 36 drug/solution combinations that are routinely used in critical care and assessed them for compatibility at varied clinical concentrations2.
The 36 medications tested were mixed together in clear plastic containers, two at a time, and inspected for optically identifiable incompatibilities before being discarded. It was discovered that 170 incompatibilities existed among the 630 combinations that were investigated (27 percent of the combinations were visibly incompatible). The research was confined to just two medications or solutions, and the interactions between them were only examined. A central line and numerous peripheral lines, it was claimed, might be used to prevent these issues. However, the possibility of an increase in complications such as sepsis and thrombophlebitis should be addressed when using extra lines. It was proposed by Kuhl that a central-venous multi-lumen catheter be used early in the treatment process in order to allow for the safe administration of possibly incompatible medications. According to a research conducted by a German pharmacist, Frank Schröder22, the use of multi-lumen catheters in combination with 0.2-micron end-line IV filters is also recommended as a technique of reducing the difficulties associated with multiple drug IV treatment. On a selection of 10 medications and three intravenous solutions at varied clinical doses, he conducted experiments in which the pH of the individual and combined solutions was measured, and the mixes were visually inspected for cloudiness and/or precipitation. The infusion regimens under investigation resulted in a variety of interactions, including the inactivation of heparin and medicines as a consequence of complex formations resulting from the incompatibility reaction of heparin, which was observed. It was also discovered that free bases were precipitating as a result of acid/base interactions. According to Schröder, the use of multi-lumen catheters with complex regimes, which are designed so that acid stable, lipid stable, and base stable formulations are administered via separate lumens, may significantly reduce the particle load resulting from incompatibility reactions in the bloodstream. As an added precaution, Schröder proposes the use of 0.2m end-line filters to eliminate further particles and pollutants that may have been introduced by parenteral solutions or disposable medical equipment. As he explains, the usage of this filter will protect the patient from potentially harmful particle loads that occur during the early phase of treatment while the patient’s infusion medication is being changed. However, although this may result in the filter getting clogged or obstructed with precipitates, it is crucial to note that the patient will be protected from this non-physiological and possibly harmful particle assault. The fact that the Pall Posidyne ELD eliminates bacterial endotoxins means that the filter and IV infusion system may be safely kept in place for up to 96 hours, according to Schröder, which can result in considerable cost and nursing time savings.
In his study proving cost and nursing time reductions using the Pall ELD96 IV filter in the intensive care unit (ICU), David Cousins, Director of Pharmacy at Derbyshire Royal Infirmary (UK), recognized the risk of drug-physico-chemical interactions and made the following observations:- Immediately upon the discovery of an incompatibility, it is critical that the infusion be halted, and that the present route of administration be evaluated and appropriate action made to correct the issue.
Practical Considerations in the Use of End-Line Filters with IV Drugs and Solutions
In addition to protecting the patient, the use of 0.2 m end-line filters will eliminate any particle material and precipitates bigger than 0.2 m in size. They will also retain any unintentional microbiological contamination and will eradicate any entrained air that may have been introduced into the infusion during processing. IV filters with a Posidyne nylon membrane will also hold endotoxin for up to 96 hours, allowing for the safe use of the filter and infusion equipment for a total of four days after the first usage.
It is suggested that all medical equipment and medications be used only after the manufacturer’s instructions for usage have been thoroughly read and understood.
Although the priming of these filters is straightforward, it is critical that all members of the team closely follow the manufacturer’s recommendations when using these filters to avoid contamination. Filters may be used to explain why and how they should be used, and in-service training can be an exceptionally valuable tool for doing so.
Flow rates and operating pressures
Filters for IV treatment have adequate capacity to retain the usual particle load associated with infusion therapy while also maintaining normal flow rates. If the particulate/precipitation load is significant, the flow rate over the filter may be decreased, and SECTION A 8 may even come to a halt if the filter membrane gets clogged. The usage of an infusion pump raises the possibility that the pressure upstream of the filter may grow, triggering the pump’s emergency shut-off function. It is necessary to examine and address the root cause(s) of the increased resistance that is contributing to the raised working pressure when the filter’s operating limitations are exceeded.
The majority of IV filter occlusions have been seen to be caused by incompatibility responses, according to experience. As mentioned by Cousins23, the recurrent clogging of end-line filters is a source of aggravation for the personnel – but the filters are doing the function for which they were built – namely, protecting the patient from infection. The filters are also showing that an incompatibility response is happening in the infusion system upstream of the filter, which has to be investigated and resolved in order for the patient to get a therapeutic dosage of the proper drug, as shown by the filters.
Colouration of filter membrane
After a long period of time has passed after the installation of an end-line filter, it is occasionally seen that the membrane has become discolored. It should be emphasized that the presence of coloration on the membrane does not always indicate the presence of a response or incompatibility, nor does it always indicate that the medication is being eliminated. It is possible that this coloration has no influence on flow rates. Some cytotoxic drugs (for example, mitoxantrone, doxorubicin HCl, daunorubicin, methotrexate) are well-known for staining membranes; yet, it has been shown that the filters do not appreciably lower the dosage delivered to the patient during treatment. When dextrose solution is injected into the membrane, this is another typical cause of membrane discoloration. Dextrose may undergo partial breakdown (caramelization) during sterilisation, resulting in the formation of degradation products (hydroxymethylfurfural), which can stain the membrane a brown color (See case 4 for further details). Nothing has to be done unless there is considerable reduction in flow or full obstruction as a result of the staining of the filter membrane (which should be done immediately).
When administering bolus quantities of medications, it is important to flush between incompatible medications. As a result, it is essential that the flushing solution be compatible with the medicine being administered. In the case of filters, the amount of fluid necessary to flush the filter chamber is about twice as large as the capacity of the filter chamber. Listed in Table 3 are the internal volumes of the Pall IV filters and their variations.