0.9% Saline or Ringer's Solution for in vivo work

0.9% Saline or Ringer's Solution for in vivo work

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A few of the labs where I currently work routinely use 0.9% saline for in vivo work (washing out debris during surgery, diluting substances for IP/IV/SC injections, etc.)

A few years ago I worked in a lab where the standard was to use Ringer's Solution. Obviously, in both labs the choice was based on an organizatorical/historical reasons. But I was wondering: Does either of these solutions perform any "better" (i.e. causes less physiological disturbances) than the other?

My guess would be Ringer's is better, since it is also suitable for keeping cells alive in vitro - and there is also this paper that calls 0.9% Saline into question altogether. But I could not really find any good comparison tests.

IV Fluids and Solutions Guide & Cheat Sheet

Get to know the different types of intravenous solutions or IV fluids in this guide and cheat sheet. Differentiate isotonic, hypertonic, and hypotonic IV solutions and the nursing interventions and management for each.

IV Administration Equipment

When a peripheral vein has a cannula inserted, an extension tubing is connected to the hub on the cannula and flushed with normal saline to maintain patency of the cannula. Most peripheral intravenous cannulas will have extension tubing, a short, 20 cm tube with a positive fluid displacement/positive pressure cap attached to the hub of the cannula for ease of access and to decrease manipulation of the catheter hub (Vancouver Coastal Health, 2008). The extension tubing must be changed each time the peripheral catheter is changed. When the peripheral cannula is not in use, the extension tubing attached to the cannula is called a saline lock.

Intravenous fluids are administered through thin, flexible plastic tubing called an infusion set or primary infusion tubing/administration set (Perry et al., 2014). The infusion tubing/administration set connects to the bag of IV solution. Primary IV tubing is either a macro-drip solution administration set that delivers 10, 15, or 20 gtts/ml, or a micro-drip set that delivers 60 drops/ml. Macro-drip sets are used for routine primary infusions. Micro-drip IV tubing is used mostly in pediatric or neonatal care, when small amounts of fluids are to be administered over a long period of time (Perry et al., 2014). The drop factor can be located on the packaging of the IV tubing.

Primary IV tubing is used to infuse continuous or intermittent fluids or medication. It consists of the following parts:

  • Backcheck valve: Prevents fluid or medication from travelling up the IV
  • Access ports: Used to infuse secondary medications and give IV push medications
  • Roller clamp: Used to regulate the speed of, or to stop or start, a gravity infusion
  • Secondary IV tubing: Shorter in length than primary tubing, with no access ports or backcheck valve when connected to a primary line via an access port, used to infuse intermittent medications or fluids. A secondary tubing administration set is used for secondary IV medication.

IV solution bags should have the date, time, and initials of the health care provider marked on them to be valid. Add-on devices (e.g., extension tubing or dead-enders) should be changed every 96 hours, if contaminated when administration set is replaced, or as per agency policy. Intravenous solution and IV tubing should be changed if:

  • IV tubing is disconnected or becomes contaminated by touching a non-sterile surface
  • Less than 100 ml is left in the IV solution bag
  • Cloudiness or precipitate is found in the IV solution
  • Equipment (date and time) is outdated
  • IV solution is outdated (24 hours since opened)

Primary and secondary administration sets (see Figure 8.4) should be changed regularly to minimize risk and prevent infection (CDC, 2011 Fraser Health Authority, 2014). Change IV tubing according to agency policy. Table 8.5 lists the frequency of IV tubing change.

Safety considerations:
  • All IV tubing must be changed using sterile technique.
  • IV tubing is changed based on the type of tubing, time used, and the type of solution.
  • If possible, coordinate IV tubing changes with IV solution changes.

Frequency of IV Tubing Change

Type of IV Tubing and Solution

How does saline water work?

Normal saline is a solution filled with electrolytes and hydrophilic molecules. It is mainly used because of its isotonic nature compared to serum plasma.

Our blood cells are bathed in plasma. Plasma is primarily comprised of sodium and chlorine ions. Sodium ions are the main electrolytes in saline water and are essential in the distribution of water and other electrolytes. Chloride ions help to facilitate binding between carbon dioxide and oxygen.

Water makes up about two-thirds of a person’s body weight. It also plays a vital role in the effectiveness of using saline water in treatment. Its distribution depends on the concentration of electrolytes in various compartments.

The primary function of saline water is to expand intravascular volume without disturbing ion concentration in the blood or causing significant fluid shifts between intravascular, intracellular, and interstitial spaces.

By restoring water levels in the body, saline water helps in the treatment of symptoms such as lightheadedness and other dehydration related symptoms.

Its high electrolyte concentration also recharges the body in incase of electrolyte loss. This is common after consuming large amounts of alcohol and in patients who are unable to get electrolytes from external sources.

Intravenous saline water is used for other purposes, too, not just treatment. For example, it is used by athletes to accelerate the rehydration process. Some people also prefer the use of saline water to hasten recovery from a hangover because it contains the electrolytes and water lost in the process of alcohol elimination.

When receiving a saline water IV injection, constant monitoring is required to ensure the IV solution is providing the right amount of fluids and minerals needed.

A condition that needs close monitoring when being given IV fluids

If you are suffering from a heart-related disease, the use of saline water injection could cause overhydration. For such a condition, the amount of intravenous fluid injected into the bloodstream should be monitored closely.

Saline water for therapy purposes

Saline water is also an essential component of intravenous therapy as it not only helps in treating the symptoms we’ve mentioned here, but it is also used in administering medication in emergencies.


The use of distilled water as an intravenous fluid is a no-go. Saline water, on the other hand, has a wide range of usage. If you are ready to get started on a healthier lifestyle or therapy, make an appointment with us. We are here to serve you. We will also answer any questions you might have.

Isotonic, Hypertonic, and Hypotonic Solutions

In this article, we will go over three types of solutions: isotonic, hypertonic and hypotonic solutions.

Before we go into the specific types, we will first go over the scenario in which the solution exists. For example, when we talk about the above solutions, these are solutions outside of a substance. For example, say if we place a cell in a solution, which is the example we will use for all the various solutions. The solution outside the cell is what we are referring to when we talk about isotonic, hypertonic, or hypotonic. The solution may be pure water or the solution may be water with a solute dissolved in it, or any such solution.

For the below examples, we will use a cell that has a NaCL concentration of 0.9%. So the water concentration inside of it is 99.1%.

Isotonic Solution

An isotonic solution is a solution in which the same amount of solute and solution is available inside of the cell and outside of the cell. The solution and solute percentage are the same inside the cell as it is in the solution outside of the cell. Therefore, using the numbers above, a cell placed in a solution of water with 0.9% NaCL is in equilibrium. Thus, the cell remains the same size. The solution is isotonic in relation to the cell.

Hypertonic Solution

A hypertonic solution is a solution that contains more solute than the cell which is placed in it. If a cell with a NaCl concentration of 0.9% is placed in a solution of water with a 10% concentration of NaCl, the solution is said to be hypertonic. Hyper means more, meaning that the solution that the cell is placed in contains more solute than the solution inside of the cell. When the solution contains more solute, this means that it contains less water. The solution outside of the cell is 10% NaCl, which means that it is 90% water. The solution inside of the cell is 0.9% NaCl, which means it is 99.1% water. Remember, solution flows from a higher concentration of water to a lower concentration of water. This is to dilute areas of higher solute concentrations, so that equilibrium can be achieved. Being that the outside solution is 90% water while the inside contains 99.1% water, water flows from the inside of the cell to the outside solution to dilute the high areas of solute concentration. Therefore, the cell loses water and shrinks.

Again, when we reference a solution to say it is hyper and hypo, we are referencing the amount of solute present in the solution in comparison to the solute inside of the cell which is in the solution. If the solution outside the cell has more solute than the solution inside of the cell, the solution is hypertonic. If the solution inside of the cell has more solute than the solution outside of the cell, the solution is hypotonic. If the solution outside of the cell contains the same solute as the solution inside of the cell, the solution is isotonic.

Hypotonic Solution

A hypotonic solution is a solution that contains less solute than the cell which is placed in it. If a cell with a NaCl concentration is placed in a solution of distilled water, which is pure water with no dissolved substances it, the solution on the outside of the cell is 100% water and 0% NaCl. Inside of the cell, the solution is 99.1% water and 0.9% NaCL. Water, again, goes from a higher concentration to a lower concentration. So water goes from the distilled water solution to the inside of the cell. As a consequence, the cell swells up and possibly bursts. Thus, putting a cell with solute in a distilled water solution will cause swelling and possible bursting of the cell.

The main way to remember all of this is that when we talk about the various solutions, we are talking in reference to the outside solution, not the solution inside of the cell. Then, next, when we talk about isotonic, hypertonic and hypotonic solutions, we can use the prefixes and suffixes to determine which is which. The suffix -tonic is in relation to the amount of solute in the solution. Hyper means more, hypo means below. So a hypertonic solution is a solution which contains more solute than the solution inside of the cell. And a hypotonic solution is a solution which contains less solute than the solution inside of the cell. This is the best way to learn this.

In vivo conditioning of acid–base equilibrium by crystalloid solutions: an experimental study on pigs

Large infusion of crystalloids may induce acid-base alterations according to their strong ion difference ([SID]). We wanted to prove in vivo, at constant PCO2, that if the [SID] of the infused crystalloid is equal to baseline plasma bicarbonate, the arterial pH remains unchanged, if lower it decreases, and if higher it increases.


In 12 pigs, anesthetized and mechanically ventilated at PCO2 ≈40 mmHg, 2.2 l of crystalloids with a [SID] similar to (lactated Ringer’s 28.3 mEq/l), lower than (normal saline 0 mEq/l), and greater than (rehydrating III 55 mEq/l) baseline bicarbonate (29.22 ± 2.72 mEq/l) were infused for 120 min in randomized sequence. Four hours of wash-out were allowed between the infusions. Every 30 min up to minute 120 we measured blood gases, plasma electrolytes, urinary volume, pH, and electrolytes. Albumin, hemoglobin, and phosphates were measured at time 0 and 120 min.


Lactated Ringer’s maintained arterial pH unchanged (from 7.47 ± 0.06 to 7.47 ± 0.03) despite a plasma dilution around 12%. Normal saline caused a reduction in pH (from 7.49 ± 0.03 to 7.42 ± 0.04) and rehydrating III induced an increase in pH (from 7.46 ± 0.05 to 7.49 ± 0.04). The kidney reacted to the infusion, minimizing the acid-base alterations, by increasing/decreasing the urinary anion gap, primarily by changing sodium and chloride concentrations. Lower urine volume after normal saline infusion was possibly due to its greater osmolarity and chloride concentration as compared to the other solutions.


Results support the hypothesis that at constant PCO2, pH changes are predictable from the difference between the [SID] of the infused solution and baseline plasma bicarbonate concentration.


Human albumin (4 to 5%) in saline is considered to be the reference colloidal solution. It is produced by the fractionation of blood and is heat-treated to prevent transmission of pathogenic viruses. It is an expensive solution to produce and distribute, and its availability is limited in low- and middle-income countries.

In 1998, the Cochrane Injuries Group Albumin Reviewers published a meta-analysis comparing the effects of albumin with those of a range of crystalloid solutions in patients with hypovolemia, burns, or hypoalbuminemia and concluded that the administration of albumin was associated with a significant increase in the rate of death (relative risk, 1.68 95% confidence interval [CI], 1.26 to 2.23 P<0.01). 17 Despite its limitations, including the small size of the included studies, this meta-analysis caused substantial alarm, particularly in countries that used large amounts of albumin for resuscitation.

As a result, investigators in Australia and New Zealand conducted the Saline versus Albumin Fluid Evaluation (SAFE) study, a blinded, randomized, controlled trial, to examine the safety of albumin in 6997 adults in the ICU. 18 The study assessed the effect of resuscitation with 4% albumin, as compared with saline, on the rate of death at 28 days. The study showed no significant difference between albumin and saline with respect to the rate of death (relative risk, 0.99 95% CI, 0.91 to 1.09 P=0.87) or the development of new organ failure.

Additional analyses from the SAFE study provided new insights into fluid resuscitation among patients in the ICU. Resuscitation with albumin was associated with a significant increase in the rate of death at 2 years among patients with traumatic brain injury (relative risk, 1.63 95% CI, 1.17 to 2.26 P=0.003). 19 This outcome has been attributed to increased intracranial pressure, particularly during the first week after injury. 20 Resuscitation with albumin was associated with a decrease in the adjusted risk of death at 28 days in patients with severe sepsis (odds ratio, 0.71 95% CI, 0.52 to 0.97 P=0.03), suggesting a potential, but unsubstantiated, benefit in patients with severe sepsis. 21 No significant between-group difference in the rate of death at 28 days was observed among patients with hypoalbuminemia (albumin level, ≤25 g per liter) (odds ratio, 0.87 95% CI, 0.73 to 1.05). 22

In the SAFE study, no significant difference in hemodynamic resuscitation end points, such as mean arterial pressure or heart rate, was observed between the albumin and saline groups, although the use of albumin was associated with a significant but clinically small increase in central venous pressure. The ratio of the volumes of albumin to the volumes of saline administered to achieve these end points was observed to be 1:1.4.

In 2011, investigators in sub-Saharan Africa reported the results of a randomized, controlled trial — the Fluid Expansion as Supportive Therapy (FEAST) study 23 — comparing the use of boluses of albumin or saline with no boluses of resuscitation fluid in 3141 febrile children with impaired perfusion. In this study, bolus resuscitation with albumin or saline resulted in similar rates of death at 48 hours, but there was a significant increase in the rate of death at 48 hours associated with both therapies, as compared with no bolus therapy (relative risk, 1.45 95% CI, 1.13 to 1.86 P=0.003). The principal cause of death in these patients was cardiovascular collapse rather than fluid overload or neurologic causes, suggesting a potentially adverse interaction between bolus fluid resuscitation and compensatory neurohormonal responses. 24 Although this trial was conducted in a specific pediatric population in an environment in which critical care facilities were limited or absent, the results call into question the role of bolus fluid resuscitation with either albumin or saline in other populations of critically ill patients.

The observations in these key studies challenge physiologically based concepts about the efficacy of albumin and its role as a resuscitation solution. In acute illness, it appears that the hemodynamic effects and effects on patient-centered outcomes of albumin are largely equivalent to those of saline. Whether specific populations of patients, particularly those with severe sepsis, may benefit from albumin resuscitation remains to be determined.


This review will be conducted in accordance with The Cochrane Collaboration [15] principles for Systematic Reviews and reported following the PRISMA guidelines [16]. This protocol was drafted in accordance with PRISMA-P guidelines (see checklist in Additional file 1) and has been registered with the PROSPERO International Prospective Register of Systematic Reviews (#CRD42016042960).

Search strategy and data sources

Our search strategy will be conducted using Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R), EMBASE Classic + Embase, Web of Science BIOSIS Previews® and EBM Reviews (including Cochrane Central databases) from inception to the moment of review. EMBASE also includes the abstract publications from major international conferences including the International Stroke Conference, Neurocritical Care Society Meeting, Society of Critical Care Medicine, and the International Symposium on Intensive Care and Emergency Medicine. A comprehensive search strategy will be constructed and implemented by a health information specialist with systematic review experience, in collaboration with the research team. MeSH terms will be used to capture each of the principal elements of the research question. We will restrict our strategy to focus on population (acute brain injury) and intervention/exposure (hypotonic crystalloid solutions and hypertonic solution alternatives—see Eligibility criteria) and will not be limited by outcome studied to increase our yield. A sample search strategy is presented in Additional file 2. Upon completion, identified citations will be exported to a cloud-based citation manager (DistillerSR v2: Systematic Review and Literature Review Software) for study selection. Manual review of the reference lists of all included studies and previous systematic reviews will be conducted. A final gray literature search will be conducted using “Google Scholar” as well as a review of the trial register (, WHO ICTRP) for any ongoing and unpublished studies. Duplicate citations will be removed. The search strategies will be kept up to date to the time of the end of the review.

Study eligibility

For the purposes of this review, we will refer to normal saline as an isotonic solution and those with lower sodium concentrations (e.g. Ringer’s Lactate, Plasma Lyte®) will be referred to as “relatively hypotonic.” Those crystalloid solutions with higher sodium concentrations (e.g., 3% saline) will be referred to as hypertonic. We will include pre-clinical studies that compare a relatively hypotonic crystalloid resuscitation fluid (Ringers Lactate, Hartmann’s or Plasma Lyte®) to an isotonic (normal saline (0.9%)) or hypertonic (i.e., hypertonic saline (3–23.4%)) crystalloid resuscitation fluid. No overtly hypotonic solution (e.g., 5% dextrose in water, 5% in 0.45% saline) or colloid solutions will be included given their very different physiological properties that would have them behave significantly differently as compared to crystalloid solutions of interest in this review.

For clinical studies, we will include observational studies that have a control group for comparison, whether prospectively or retrospectively conducted, and intervention studies (e.g., randomized controlled trials). An iterative process for study selection will be followed using the criteria set out in Table 1.

Study selection process

All records will first be screened by title and abstract. All citations clearly not relevant to the review (e.g., wrong population and narrative review) will be excluded. This process will be performed in duplicate by two independent reviewers. Any citation in which an abstract is not available and where suitability for inclusion is questioned will proceed to the next stage. All citations not excluded in the first screen will have full articles retrieved for a second review, in duplicate by independent reviewers, and the selection criteria applied. Any differences in classification between the two independent reviewers will be reviewed and consensus decision made. A third independent senior reviewer will be used in any instance in which consensus is not reached.

Data extraction

A data extraction form will be prepared a priori in MS Excel (Microsoft Corporation, Seattle, Washington) and piloted prior to duplicate extraction by two independent reviewers. The data extraction form will be designed to capture information regarding study characteristics, design, and methods (i.e., title, authors, journal/source, year of publication, country, type of study, study period, total number of subjects, case ascertainment and/or inclusion/exclusion criteria, randomization, allocation concealment and blinding methods (where applicable)) study population characteristics (i.e., clinical studies: age, sex, primary neurological diagnosis, injury severity/characteristics, comorbidities pre-clinical studies: species, species detail, age, sex, weight, model type and experimental conditions, injury severity/characteristics) interventions and co-interventions [crystalloid resuscitation fluid type, dose, frequency, adjunctive fluid administration, use of a management protocol, use of co-interventions for intracranial pressure management strategies (including hyperosmolar therapy, paralysis, hyperventilation, barbiturate coma, decompression)] and outcome (our pre-defined primary, secondary and tertiary outcomes).

Outcome data will be extracted based on a priori specified time points and dosage format. Given fluid resuscitation is the intervention of interest, data will be extracted for early (0–6 h at hourly time points) and delayed resuscitation (up to 7 days post-injury at 12, 24, 48, etc. hours) in order to evaluate both the immediate and delayed effects of treatment. Data will then be pooled by dosage format [means of administration (bolus vs maintenance infusion) and total dose] for the purposes of analysis.

Disagreements in data extraction will be resolved by consensus or by a third reviewer with methodologic and clinical expertise as required. If there are missing data, the corresponding authors of the studies will be contacted and if the data is not located, the remaining available data will be analyzed. The possible impact of the missing data will then be discussed as a limitation.

Risk of bias

Risk of bias will be assessed using the Newcastle-Ottawa Scale [17] for observational studies, the Cochrane Collaboration tool for assessing the risk of bias in randomized controlled trials (RCTs) [18] and SYRCLE’s risk of bias tool for animal studies [19]. Bias risk assessment will be completed in a similar fashion as the study selection process: in duplicate by two independent assessors. Cases of discordance not resolved by consensus will be reviewed by a third senior assessor. Risk of bias assessment of all included studies will be summarized and presented in table format. Low risk of bias will be defined as those studies with score of ≥ 7 using the Newcastle-Ottawa Scale, those deemed low risk across all domains of the Cochrane Collaboration’s tool for assessing risk of bias, or those receiving an overall “yes” judgment across all signaling questions used in SYRCLE’s risk of bias tool. The authors recognize that no formal cut-offs exist to define low or high risk of bias with the Newcastle-Ottawa Scale however, we deem that in order for low risk of bias to exist in an observational study, there must be excellent reporting, high internal and external validity with little risk of confounding such that high scores in each of these domains are necessary to meet low-risk criteria.

Patient and public involvement

No patients were involved in the creation of this protocol.

Daptomycin: a comparison of two intravenous formulations

Merck & Co., Inc., Kenilworth, NJ, USA

Daptomycin is a cyclic lipopeptide antibacterial agent with potent bactericidal activity against a broad range of Gram-positive organisms. In 2003, daptomycin for injection received approval from the US Food and Drug Administration (FDA) for the treatment of patients with complicated skin and skin structure infections (cSSSIs) in 2006, it was approved for the treatment of patients with Staphylococcus aureus bacteremia, including those with right-sided infective endocarditis caused by methicillin-susceptible and methicillin-resistant isolates. In 2016, the FDA approved a new formulation of daptomycin for injection (daptomycin RF) for the same indications. The efficacy and safety of daptomycin for injection have been established in pivotal clinical trials, and the findings of nonclinical studies indicate that both formulations of daptomycin for injection are equivalent. Herein we refer to the new daptomycin formulation as daptomycin RF to distinguish it from the original formulation. Daptomycin RF provides clinicians and clinical pharmacists with a product that offers improved stability and more rapid, in-vial reconstitution with either sterile or bacteriostatic water for injection, while maintaining the same antibacterial coverage. Here we discuss the rationale for and the potential value of daptomycin RF, and briefly review the similarities and differences between the original formulation of daptomycin and daptomycin RF.

MRSA, drug stability, Gram-positive bacterial infections, bacteremia, antibiotics, formulation

Daptomycin is an intravenously administered antibiotic. Daptomycin, first approved by the US Food and Drug Administration (FDA) in 2003, is effective against a broad range of bacterial infections, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). Daptomycin has been used to treat patients with bacterial infections of the skin and underlying tissues as well as infections that have entered the bloodstream. Daptomycin is provided by the manufacturer as a powder that requires mixing with a liquid before injection. In 2016, the FDA approved a new formulation of daptomycin (daptomycin RF) that shortens the time required to dissolve the powder into a solution and improves the use period of the prepared solution, while maintaining the antibiotic’s strength to fight the same types of bacterial infections. This article highlights the differences in the new formulation, compared with the original. Key differences of the new formulation include: 1) The powder can be stored at room temperature. 2) It is quicker and easier to prepare the injection/infusion solution from the powder. 3) The powder should be dissolved in sterile or bacteriostatic water instead of saline solution. 4) It has a longer use period of injection/infusion solution – both at room temperature or with refrigeration.

Daptomycin is a cyclic lipopeptide antibacterial agent with potent bactericidal activity against a broad range of Gram-positive organisms. 1,2 On the basis of 2 pivotal randomized, controlled, Phase III clinical trials, the US Food and Drug Administration (FDA) approved daptomycin for injection (Cubicin® Merck & Co., Inc., Kenilworth, NJ, USA) for the treatment of complicated skin and skin structure infections (cSSSIs) caused by certain Gram-positive bacteria in 2003 and for the treatment of Staphylococcus aureus bloodstream infections (bacteremia), including right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates in 2006. 4𔃄

Stability, extended use period, and reduced reconstitution time are the important attributes for a lyophilized antibacterial agent intended for intravenous (IV) administration. A new formulation of daptomycin for injection (daptomycin RF) has been developed that provides improved stability (eg, room temperature storage) and faster reconstitution time, while maintaining the same antibacterial coverage as the original formulation. 4,7 In 2016, the FDA approved daptomycin RF (Cubicin RF Merck & Co., Inc.) for the same indications as those of the original daptomycin formulation. 3,7 Both formulations of daptomycin also received approval in 2017 for the treatment of cSSSIs and S. aureus bloodstream infections (bacteremia) in pediatric patients (aged 1󈝽 years).

Here we review the rationale for and the potential value of daptomycin RF, highlighting its similarities to and differences from the original approved formulation of daptomycin, and improvements that have been made to its product-handling characteristics.

Similarities and differences between daptomycin and daptomycin RF

Formulation, stability, and reconstitution

Table 1 summarizes the major differences between daptomycin and daptomycin RF. 4,7 Daptomycin RF has the same indication, dosage form (lyophilized in-vial presentations and 500 mg strength in the USA), and administration recommendations for adults (2 minutes for IV injection 30 minutes for IV infusion) as the original formulation of daptomycin. However, pediatric patients should only receive daptomycin by IV infusion for 30 minutes, regardless of formulation. 4,7 The active ingredient of both daptomycin RF and daptomycin is the same, but the formulations are not identical.

Table 1 Major differences between daptomycin and daptomycin RF
Notes: Data from package inserts of Cubicin® (daptomycin for injection) 4 and Cubicin® RF (daptomycin for injection). 7 a Osmolality refers to the number of solute particles per kilogram of water osmolarity refers to the number of solute particles per liter of water. Osmolarity is considered roughly equivalent to osmolality (ie, 1 L is approximately equal to 1 kg) because normal saline is a dilute aqueous solution with a specific gravity of 1.0003. b Room temperature = 20°C󈞅°C (68°F󈞹°F). c Refrigerated temperature = 2°C𔃆°C (36°F󈞚°F). d Storage period is determined by sterility rather than stability of reconstituted product. Daptomycin RF is a new formulation of daptomycin for injection.
Abbreviations: IV, intravenous N/A, not applicable.

Two key differences between the formulations are the addition of sucrose as an inactive ingredient and an increased target pH (6.8 vs 4.7) in daptomycin RF that is achieved during manufacturing through titration with sodium hydroxide. 4,7 The addition of sucrose enhances the shelf stability of daptomycin RF, permitting the storage of the lyophilized powder vial at controlled room temperature (20°C󈞅°C) rather than under refrigeration (5°Cۭ°C) refrigerated storage is required for the original formulation of daptomycin. 4,7

The increased pH of daptomycin RF reduces reconstitution time compared with daptomycin (Ӯ vs ㅇ minutes, respectively). Preparation of daptomycin requires gentle rotation after the addition of diluent, followed by a 10-minute rest period and a further swirling to ensure thorough reconstitution vigorous agitation is discouraged to minimize foaming. Preparation of daptomycin RF is far less complex and only requires gentle rotation or swirling for a few minutes to completely reconstitute the lyophilized powder. 4,7

Furthermore, the diluent for vial reconstitution of daptomycin RF has been changed from 0.9% sodium chloride to sterile or bacteriostatic water for injection due to the addition of sucrose. 4,7 This change is particularly useful in the context of historic saline shortages, where daptomycin RF can also be administered through IV injection over a 2-minute period using sterile or bacteriostatic water for injection if 0.9% sodium chloride is not available. 7 Use of a saline diluent for reconstitution of daptomycin RF may result in a hypertonic solution, increasing the risk for injection site irritation if administered by 2-minute IV injection. However, a 0.9% sodium chloride diluent can still be used with daptomycin RF when the reconstituted product is further diluted in an IV bag. 7 In the case that sterile or bacteriostatic water for injection is not available, the original daptomycin formulation may be used, as it requires reconstitution in 0.9% sodium chloride alone. 4

The reformulation of daptomycin has yielded a more stable product in daptomycin RF. Daptomycin RF has a longer in-use shelf period although times vary based on dosage form (vial, IV bag, or syringe) and diluent used. 4,7 For example, daptomycin RF reconstituted in the vial with bacteriostatic water or sterile water and subsequently refrigerated has an in-use storage period of 3 days, and daptomycin RF reconstituted in the vial with sterile water and stored at room temperature has an in-use storage period of 1 day. 7 In contrast, the original formulation must be refrigerated prior to reconstitution, and the diluted solution has an in-use storage period of 48 hours with refrigeration. 4 In order to reduce confusion if both products are available in the same location, the product packaging features a blue cap for daptomycin and a purple cap for daptomycin RF.

Compatibility of daptomycin

Daptomycin is compatible with 0.9% sodium chloride solution and lactated Ringer’s solution. 4 Daptomycin RF is chemically compatible with sterile water for injection, bacteriostatic water for injection, 0.9% sodium chloride solution, or lactated Ringer’s solution however, initial reconstitution should only occur with sterile or bacteriostatic water for injection due to osmolality constraints and to prevent injection site irritation. 7 Both daptomycin and daptomycin RF are incompatible with dextrose-containing diluents and should not be used in conjunction with ReadyMED (Reliant Medical Group, Worcester, MA, USA) elastomeric infusion pumps (impurity identified). 4,7

Physical and chemical potency analyses demonstrated that daptomycin was stable and compatible when admixed with commonly administered IV medications, including aztreonam, ceftazidime, ceftriaxone, dopamine, gentamicin, fluconazole, heparin, levofloxacin, and lidocaine. 8 However, unpublished studies conducted by Merck demonstrated that both daptomycin and daptomycin RF reconstituted solutions were incompatible when admixed with reconstituted vancomycin (data on file, Merck & Co., Inc.).

Establishing the equivalence of daptomycin RF and daptomycin

Evidence of clinical equivalence between the daptomycin and daptomycin RF formulations was obtained through comparative evaluation of data generated from a series of in vitro studies and through evaluation of the available literature these findings were presented to the FDA before it granted approval for daptomycin RF. 3 The justifications supporting the clinical equivalence of daptomycin RF and daptomycin can be articulated as follows:

  1. Per the Code of Federal Regulations 21CFR320.22(b)(1), the in vivo bioequivalence of a drug product may be considered self-evident if it is a parenteral solution intended solely for administration by injection and contains the same active and inactive ingredients in the same concentrations as the approved drug product. 9 Daptomycin RF is a parenteral solution intended solely for IV infusion and, following reconstitution, contains the same daptomycin drug concentration as the current marketed product therefore, the in vivo bioequivalence is self-evident for this formulation. However, the impact of the additional formulation adjustments must also be taken into consideration (eg, addition of sucrose). To that end, an additional literature research and additional studies were conducted as described in justifications 2𔃄. 3
  2. The potential for differences in pharmacokinetic (PK) parameters between the 2 formulations was also evaluated in a crossover PK animal study (beagle dogs). 3 This model has been used effectively to translate the exposure–response relationship for skeletal muscle safety to the clinical situation. A single IV bolus injection of 15 mg/kg diluted in either distilled water (daptomycin RF) or saline (daptomycin) was delivered to 6 male dogs on Day 1 followed by another single IV bolus injection of the same dilutions on Day 8. Plasma concentrations were assessed from samples taken at time points from 2 minutes to 24 hours post injection. There were no significant differences between daptomycin RF and daptomycin in the plasma concentrations, area under the concentration–time curve from time zero extrapolated to infinity (AUC0–8 768 vs 807 μg×h/mL), or maximum plasma concentration (Cmax 258 vs 257 μg/mL). Likewise, no differences were detected between daptomycin RF and daptomycin in the mean values for plasma clearance (0.33 vs 0.32 mL/min/kg), volume of distribution at steady state (80 vs 90 mL/kg), and terminal elimination half-life (2.8 vs 3.4 hours). The findings of this study indicated that the PK of daptomycin RF was unchanged compared with that of daptomycin, demonstrating the comparability of the 2 formulations. 3
  3. A 2-week toxicity and toxicokinetic study was conducted in rats to identify potential changes to the nonclinical safety profile of sucrose-based daptomycin RF. The highest tolerated dose of 100 mg/kg was administered to 2 male and 2 female rats. At this dose, no mortality or clinical signs were detected for up to 24 hours after dosing so 100 mg/kg was selected as the high dose for a 2-week study. Ten rats per group were dosed once daily for 14 days with either daptomycin RF or daptomycin at concentrations of 0, 25, 50, or 100 mg/kg/day. For both groups at all doses, there were no deaths, clinical signs observed, or changes in body weight or food consumption. Hematology/coagulation, clinical chemistry, and urine analysis findings were not significant or toxicologically relevant. Toxicokinetic parameters including area under the concentration–time curve from time 0 to 24 hours (AUC0󈞄), and Cmax were similar between daptomycin RF and daptomycin. Further, a comparison of hemolytic potential of the 2 formulations showed no difference in any tested concentration (50� μg/mL). Overall, findings for daptomycin RF were comparable to previous results with the original formulation. All changes of toxicologic significance were previously noted in rats and were not significantly impacted by daptomycin RF. 3,4
  4. Per the Code of Federal Regulations 21CFR320.22(d)(4), bioequivalence of a drug product may be measured in vitro in lieu of clinical data if it is a reformulated product that is identical except for a different color, flavor, or preservative that could not affect its bioavailability. 9 Physicochemical compatibility data demonstrated that there were no interactions between daptomycin and the added excipients (ie, sucrose) that could affect the bioavailability of the product. Furthermore, in vitro studies demonstrated no difference in protein binding or microbiologic potency between daptomycin RF and daptomycin. Specifically, plasma protein binding was evaluated via equilibrium dialysis, and at 10 and 100 μg/mL of daptomycin, both formulations showed nearly identical percentages of protein binding, ranging between 89.3% and 93.2% at the lower concentration and 94.4%󈟋.3% at the higher concentration. 3 Taken together, these data indicate that free drug concentration and microbiologic activity are similar between the two formulations hence, efficacy is also expected to be similar.
  5. The sole additional inactive ingredient in daptomycin RF is sucrose, which is generally recognized as safe and is commonly used in many FDA-approved parenteral drug products. Thorough evaluation of the available literature did not reveal any evidence that the amount of sucrose in daptomycin RF would impact the distribution or elimination of daptomycin. In addition, the sucrose level on reconstitution of daptomycin RF in a vial is 7.5% weight per volume (wt/vol), which is well below the maximum acceptable level of sucrose in a drug product for administration by IV injection (19.5% wt/vol), as indicated by the FDA’s Inactive Ingredient Database (IID). 10 The IID provides information (eg, route, dosage form, and maximum potency) on inactive ingredients in FDA-approved drug products an inactive ingredient that is approved and included in the IID at a certain dosage form and potency may be considered safe if it is used in a similar manner for a similar type of drug product (eg, IV administration by injection). 10 Furthermore, the amount of sucrose that would be administered to an average 80 kg patient taking daptomycin RF 6 mg/kg is 4.8 g/week, which is well below the threshold for renal injury of 1 g/kg per week in an 80 kg patient with renal insufficiency. 11 In addition, the amount of sucrose on reconstitution of daptomycin RF (0.75 g in 10 mL sterile water for injection) is not anticipated to have a clinically meaningful impact on blood glucose in patients. Earlier studies have found no impact on blood glucose levels after oral intake of sucrose at doses of 15󈞅 g in patients with well-controlled or poorly controlled diabetes. 12,13
  6. The pH and osmolality of daptomycin RF were evaluated for potential issues related to compatibility with blood and local tolerability at the injection site. 3 The higher pH of daptomycin RF suggests greater compatibility with physiologic pH, with no impact on bioavailability. Although the osmolality of daptomycin RF is increased, it remains within a compatible range for infusion when daptomycin is reconstituted correctly and is not considered to have a clinically meaningful impact on the tolerability of the new IV formulation. 3
  7. In vitro studies, dilution compatibility studies, and stability studies comparing daptomycin RF and daptomycin were conducted. The findings of these studies indicated that the dilution compatibility of reconstituted daptomycin RF with sterile or bacteriostatic water for injection, 0.9% sodium chloride, or lactated Ringer’s solution was equivalent or better than that of daptomycin.
  8. Product stability and degradation profile remained comparable or better with daptomycin RF vs daptomycin.

Collectively, these data demonstrated the comparability of daptomycin RF with daptomycin, and in 2016, the FDA approved daptomycin RF for the same indications and for use in the same manner as daptomycin. 3,4,7

Daptomycin RF is an alternative option for the treatment of patients with cSSSIs and S. aureus bloodstream infections this new formulation is available in the USA and Canada. The efficacy and safety of daptomycin for injection have been established in pivotal clinical trials, and the findings of nonclinical studies indicate that both formulations of daptomycin for injection are equivalent. In the outpatient setting, the improved time to reach complete solution during reconstitution requires less nursing attention for the overall process, and a pH closer to physiologic values will continue to support the usefulness of daptomycin RF in this setting as either an IV injection or infusion. In addition, room temperature storage conditions and shorter reconstitution times may make daptomycin RF more easily used in an outpatient setting such as a hemodialysis clinic (note: when possible, daptomycin RF should be administered following the completion of hemodialysis). 7

In conclusion, this new formulation provides patients and health care providers (eg, physicians and clinical pharmacists) with a therapeutic option that offers greater stability and requires less time for reconstitution.

The authors thank Sonia Atzingen of Merck & Co., Inc., Kenilworth, NJ, USA, for her contributions to this research. Medical writing and editorial assistance were provided by Maxwell Chang, BSc(Hons), and Timothy A. Becker, PharmD, ApotheCom, Yardley, PA, USA. This assistance was funded by Merck & Co., Inc.

All authors contributed toward data analysis, drafting, and critically revising the paper gave final approval of the version to be published and agreed to be accountable for all aspects of the work.

All authors are employees of Merck & Co., Inc., Kenilworth, NJ, USA. The authors report no other conflicts of interest in this work.

Sauermann R, Rothenburger M, Graninger W, Joukhadar C. Daptomycin: a review 4 years after first approval. Pharmacology. 200881(2):79󈟇.

Gonzalez-Ruiz A, Seaton RA, Hamed K. Daptomycin: an evidence-based review of its role in the treatment of Gram-positive infections. Infect Drug Resist. 20169:47󈞦.

US Food and Drug Administration (Center for Drug Evaluation and Research). Approval Package for NDA 21-572/S-052 (Cubicin RF). 2016.

Cubicin ® (daptomycin for injection) for intravenous use [package insert]. Whitehouse Station, NJ: Merck & Co., Inc. 2017.

Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BI Daptomycin 98-01 and 99-01 Investigators. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 200438(12):1673�.

Fowler VG Jr, Boucher HW, Corey GR, et al S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006355(7):653�.

Cubicin ® RF (daptomycin for injection) for intravenous use [package insert]. Whitehouse Station, NJ: Merck & Co., Inc. 2017.

Lai JJ, Brodeur SK. Physical and chemical compatibility of daptomycin with nine medications. Ann Pharmacother. 200438(10):1612�.

US Government Publishing Office. Procedures for determining the bioavailability or bioequivalence of drug products. Available from:ɤc4f1e03168ddbafbe6af73b46e6a567&mc=true&node=se21.5.320_122&rgn=div8. Accessed June 8, 2017.

US Food and Drug Administration. Inactive ingredient search for approved drug products: frequently asked questions. Available from: Updated July 14, 2017. Accessed June 8, 2017.

Ahsan N, Palmer BF, Wheeler D, Greenlee RG Jr, Toto RD. Intravenous immunoglobulin-induced osmotic nephrosis. Arch Intern Med. 1994154(17):1985�.

Bornet F, Haardt MJ, Costagliola D, Blayo A, Slama G. Sucrose or honey at breakfast have no additional acute hyperglycaemic effect over an isoglucidic amount of bread in type 2 diabetic patients. Diabetologia. 198528(4):213�.

Chantelau EA, Gosseringer G, Sonnenberg GE, Berger M. Moderate intake of sucrose does not impair metabolic control in pump-treated diabetic out-patients. Diabetologia. 198528(4):204�.

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Oral Rehydration Therapy

O ver the past four decades, oral rehydration has been demonstrated to be quite effective in replacing diarrheal fluid losses. This therapy is best reserved for the child with mild or moderate dehydration.

The intestine (both the small bowel and colon) is remarkably efficient in its ability to absorb water. The small bowel absorbs the vast majority of the body's fluid needs.

Oral Rehydration Therapy (ORT) is accepted as the standard of care and first line treatment for the management of acute gastroenteritis with or without mild to moderate dehydration.

  • Total osmolality between 200 and 310 mOsm/L
  • Equimolar concentrations of glucose and sodium
  • Glucose concentration <20 g/L (111 mmol/L)
  • Sodium concentration between 60 and 90 mEq/L
  • Potassium concentration between 15 and 25 mEq/L
  • Citrate concentration between 8 and 12 mmol/L
  • Chloride concentration between 50 and 80 mEq/L

There are commercially available preparations that approximate these concentrations such as Pedialyte, Enfalyte, and Rehydralyte.

Note: Patients with mild to moderate dehydration can be treated with ORT. Those with severe dehydration are not candidates and need IV infusions. Also, those patients with altered mental status who may be at risk for aspiration and those patients with intestinal diseases such as short gut or ileus are also not candidates. Vomiting is not a contraindication for ORT.

Phases of Oral Rehydration Therapy

ORT encompasses two phases of treatment

During both phases, fluid losses from vomiting and diarrhea are replaced in an ongoing manner. An age-appropriate, unrestricted diet should also be instituted after the dehydration is corrected. If the patient is breastfed, breastfeeding should continue during this phase as well as during the maintenance phase. Formula-fed infants should continue their usual formula immediately upon rehydration. Lactose-free or lactose-reduced formulas usually are unnecessary. The BRAT (banana-rice-applesauce-toast) diet is unnecessarily restrictive and can provide suboptimal nutrition.

How to Administer Oral Rehydration Therapy

ORS is administered in frequent, small amounts of fluid by spoon or syringe. A nasogastric tube can be used in the child who refuses to drink. Nasogastric (NG) feeding allows continuous administration of ORS at a slow, steady rate for patients with persistent vomiting. For those with vomiting, the majority can be rehydrated successfully with oral fluids if limited volumes of ORS (5 mL) are administered every 5 minutes, with a gradual increase in the amount consumed

Mild to moderate dehydration:

Rehydration phase:The dose is 50-100 ml/kg over 3-4 hours.

During both phases, ongoing losses from diarrhea and vomiting are replaced with ORS. If the losses can be measured accurately, 1 mL of ORS should be administered for each gram of diarrheal stool. Alternatively, 10 mL/kg of body weight of ORS should be administered for each watery or loose stool, and 2 mL/kg of body weight for each episode of emesis.

Severe dehydration:

Severe dehydration is a medical emergency, and requires emergent IV therapy with rapid infusion of 20 mL/kg of isotonic saline. As the patient's condition improves, therapy can be later changed to ORT.


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