LMD Injection

LMD (dextran 40) is a sterile, nonpyrogenic preparation of low molecular weight dextran (average mol. wt. 40,000) in 5% Dextrose Injection or 0.9% Sodium Chloride Injection. It is administered by intravenous infusion.

Also described as low viscous or low viscosity dextran, dextran 40 is prepared by acid hydrolysis and differential fractionation of a crude macromolecular polysaccharide produced from the fermentation of sucrose by the bacterium, Leuconostoc mesenteroides (strain B-512). The crude material is composed of linked glucose units. In the fraction represented by dextran 40, 80% of the molecules have a molecular weight ranging from 10,000 to 90,000 (average approximately 40,000) when measured by a light scattering method. More than 90% of the linkages are of the 1,6 alpha glucosidic, straight chain type.

Each 100 mL of 10% LMD (dextran 40) in 5% Dextrose Injection contains 10 g dextran 40 and 5 g dextrose hydrous in water for injection. Total osmolar concentration is 255 mOsmol/liter (calc.); pH is 4.4 (3.0 to 7.0).

Each 100 mL of 10% LMD (dextran 40) in 0.9% Sodium Chloride Injection contains 10 g dextran 40 and 0.9 g sodium chloride in water for injection. Total osmolar concentration is 310 mOsmol/liter (calc.); pH is 4.9 (3.5 to 7.0) (may contain sodium hydroxide and/or hydrochloric acid for pH adjustment). Electrolyte concentration per liter: Na+ 154 mEq; Cl- 154 mEq (not including ions for pH adjustment).

The solutions contain no bacteriostat, antimicrobial agent or added buffers (except for pH adjustment) and are intended only for single-dose injection. When smaller doses are required the unused portion should be discarded.

10% LMD (dextran 40) is an artificial colloid pharmacologically classified as a plasma volume expander; 5% Dextrose Injection is a fluid and nutrient replenisher; 0.9% Sodium Chloride Injection is a fluid and electrolyte replenisher.

Dextran 40 is a linear glucose polymer (polysaccharide) chemically designated (C6 H10 O5)n.

The structural formula for dextran (repeating unit) is:

Dextrose, USP is chemically designated D-glucose monohydrate (C6 H12 O6 • H2O), a hexose sugar freely soluble in water.

Sodium Chloride, USP is chemically designated NaCl, a white crystalline powder freely soluble in water.

Water for Injection, USP is chemically designated H2O.

The flexible plastic container is fabricated from a specially formulated polyvinylchloride. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions inside the plastic container also can leach out certain of the chemical components of the plastic in very small amounts before the expiration period is attained. However, safety of the plastic has been confirmed by tests in animals according to USP biological standards for plastic containers.

LMD (dextran 40) is contraindicated in patients with known hypersensitivity to dextran, in those with marked hemostatic defects of all types (thrombocytopenia, hypofibrinogenemia, etc.) including those caused by drugs (heparin, warfarin, etc.), marked cardiac decompensation and in renal disease with severe oliguria or anuria.

Although infrequent, severe and fatal anaphylactoid reactions consisting of marked hypotension or cardiac and respiratory arrest have been reported, most of these reactions have occurred in patients not previously exposed to intravenous dextran and early in the infusion period. It is strongly recommended, therefore, that patients not previously exposed to dextran be observed closely during the first minutes of the infusion period.

Anaphylactoid Reactions

There have been rare reports of serious and life-threatening dextran-induced anaphylactoid reactions (DIAR) associated with Dextran 40 and Dextran 70 administration. To reduce the likelihood of DIAR, 20 mL dextran 1 should be administered prior to infusion of Dextran 40 or Dextran 70 consistent with the dextran 1 package insert.1-5 See DOSAGE AND ADMINISTRATION. Investigators have reported a 35-fold decrease (from 1:2000 to 1:70,000) in the incidence of DIAR following prophylactic use of dextran 1.6 However, serious and life-threatening reactions may still occur following initiation of an infusion of any clinical dextran (see ADVERSE REACTIONS).

Because of the seriousness of anaphylactoid reactions, it is recommended that the infusion of intravenous dextran be stopped at the first sign of an allergic reaction provided that other means of sustaining the circulation are available. Resuscitative measures should be readily available for emergency administration in the event such a reaction occurs. In circulatory collapse due to anaphylaxis, rapid volume substitutions with an agent other than dextran should be instituted.

Because LMD (dextran 40) is a hypertonic colloid solution, it attracts water from the extravascular space. This shift of fluid should be considered if the drug is used for poorly hydrated patients where additional fluid therapy will be needed. If LMD is given in excess, vascular overload could occur. The latter possibility can be avoided with careful clinical monitoring preferably by central venous pressure.

Renal excretion of LMD causes elevations of the specific gravity of the urine. In the presence of adequate urine flow only minor elevation will occur, whereas in patients with reduced urine output, urine viscosity and specific gravity can be increased markedly. Since urine osmolarity is only slightly increased by the presence of dextran molecules, it is recommended that, when desired, a patient’s state of hydration be assessed by determination of urine or serum osmolarity. If signs of dehydration are present, additional fluid should be administered. An osmotic diuretic such as mannitol also can be used to maintain an adequate urine flow.

Although numerous studies attest to the “nephrotonic” effect of LMD, renal failure has been reported to occur after the use of LMD.

Evidence of tubular vacuolization (osmotic nephrosis) has been found following LMD administration in animals and man. While this appears to be reversible experimentally in animals and to be a consequence of high urine concentration of the drug, its exact clinical significance is presently unknown.

Occasional abnormal renal and hepatic function values have been reported following administration of LMD. However, the specific effect of LMD on renal and hepatic function could not be determined because most of the patients also had undergone surgery or cardiac catheterization. A comparative study of dextran 40 and 5% dextrose in water as pump-priming fluids in open-heart surgery has shown similar elevations of serum glutamic oxaloacetic transaminase (SGOT), aspartate aminotransferase and serum glutamic pyruvic transaminase (SGPT), alanine aminotransferase values in both groups.

Caution should be employed when LMD is administered to patients with active hemorrhage as the resulting increase in perfusion pressure and improved microcirculatory flow may result in additional blood loss.

Administering infusions of LMD that exceed the recommended dose should be avoided, since a dose-related increase in the incidence of wound hematoma, wound seroma, wound bleeding, distant bleeding (hematuria and melena) and pulmonary edema has been observed. Recommended doses should never be exceeded in patients with advanced renal disease, since excessive doses may precipitate renal failure.

Dextran may interfere to some extent with platelet function and should be used with caution in cases with thrombocytopenia. Transient prolongation of bleeding time and/or slightly increased bleeding tendency may occur with the administration of doses greater than 1,000 mL. Care should be taken to prevent a depression of hematocrit below 30% by volume. When large volumes of dextran are administered, plasma protein levels will be decreased.

Solutions containing sodium ions should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention.

The intravenous administration of this solution can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of administered parenteral solutions.

The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentrations of such solutions.

In patients with diminished renal function, administration of solutions containing sodium ions may result in sodium retention.

The possibility of circulatory overload should be kept in mind. Special care should be exercised in patients with impaired renal clearance of dextran. When the risk of pulmonary edema and/or congestive heart failure may be increased, dextran should be used with caution.

In patients with normal hemostasis, dosage of LMD (dextran 40) approximating 15 mL/kg of body weight may prolong bleeding time and depress platelet function. Dosages in this range also markedly decrease factor VIII, and decrease factors V and IX to a greater degree than would be expected to occur from hemodilution alone. Since these changes tend to be more pronounced following trauma or major surgery, patients should be observed for early signs of bleeding complications.

Since increased rouleaux formation may occur in the presence of dextran, it is recommended that blood samples be drawn for typing and cross-matching prior to the infusion of dextran and reserved for subsequent use if necessary. If blood is drawn after infusion of dextran, the saline agglutination and indirect antiglobulin methods may be used for typing and cross-matching. Difficulty may be encountered when proteolytic enzyme techniques are used to match blood.

Consideration should be given to withdrawal of blood for chemical laboratory tests prior to initiating therapy with dextran because of the following:

Solutions containing dextrose should be used with caution in patients with known subclinical or overt diabetes mellitus.

Caution must be exercised in the administration of parenteral fluids, especially those containing sodium ions, to patients receiving corticosteroids or corticotropin.

Do not administer unless solution is clear and container is undamaged. Discard unused portion.

Drug Interactions. Additive medications should not be delivered via plasma volume expanders.

Pregnancy Category C. Animal reproduction studies have not been conducted with dextran 40 in dextrose or sodium chloride. It is also not known whether dextran 40 in dextrose or sodium chloride can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. 10% LMD (dextran 40) in dextrose or sodium chloride should be given to a pregnant woman only if clearly needed.

Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when 10% LMD (dextran 40) in dextrose or sodium chloride is administered to a nursing woman.

Pediatric Use. The safety and effectiveness of dextran 40 have not been established in neonates. Its limited use in neonates has been inadequate to fully define proper dosage and limitations for use.

Antigenicity of dextrans is directly related to their degree of branching. Since LMD (dextran 40) has a low degree of branching, it is relatively free of antigenic effect. However, a few individuals have experienced mild urticarial reactions. More severe reactions, consisting of severe anaphylactoid reaction, generalized urticaria, tightness of the chest, wheezing, hypotension, nausea and vomiting may occur in rare instances. Symptoms and signs of adverse systemic reaction may be relieved by parenteral administration of antihistamines, ephedrine or epinephrine, while other means of shock therapy are instituted. The route of administration and dosages of the therapeutic agent selected will depend upon the severity and rapidity of progression of the reaction.

Reactions which may occur because of the solution or the technique of administration include febrile response, infection at the site of injection, venous thrombosis or phlebitis extending from the site of injection, extravasation and hypervolemia.

If an adverse reaction does occur, discontinue the infusion, evaluate the patient, institute appropriate therapeutic countermeasures, and save the remainder of the fluid for examination if deemed necessary (see WARNINGS for treatment of anaphylactic shock).

Post Marketing

Severe reactions have been observed with Dextran 40 and Dextran 70. Reported reactions include: generalized urticaria, nausea and vomiting, wheezing, hypotension, shock and cardiac arrest (dextran-induced anaphylactoid reactions, DIAR). FDA has received 94 reports of severe DIAR since 1964. Because these reactions are reported voluntarily and the treated population is of indeterminate size, the frequency of reactions cannot be estimated reliably.