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The hyaluronidases (EC are a family of enzymes that degrade hyaluronic acid.

The enzyme increases tissue permeability, and consequently is used in conjunction with other drugs, to speed their dispersion and delivery. The most common example is opthalmic surgery, where it is used in combination with local anesthetics.

Some bacteria produce hyaluronidase.

In human fertilization, hyaluronidase is released by the acrosome of the sperm cell after it has reached the oocyte. Hyaluronidase aids in digesting proteins in the zona pellucida, thus enabling conception.

Brand names include Vitrase® (ISTA Pharmaceuticals) and Wydase®.


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Hypodermoclysis: An Alternative Infusion Technique
From American Family Physician, 11/1/01 by Menahem Sasson

Hypodermoclysis, the subcutaneous infusion of fluids, is a useful and easy hydration technique suitable for mildly to moderately dehydrated adult patients, especially the elderly. The method is considered safe and does not pose any serious complications. The most frequent adverse effect is mild subcutaneous edema that can be treated by local massage or systemic diuretics. Approximately 3 L can be given in a 24-hour period at two separate sites. Common infusion sites are the chest, abdomen, thighs and upper arms. The preferred solution is normal saline, but other solutions, such as half-normal saline, glucose with saline or 5 percent glucose, can also be used. Potassium chloride can be added to the solution bag if needed. Hyaluronidase can also be added to enhance fluid absorption. Hypodermoclysis can be administered at home by family members or a nurse; the technique should be familiar to every family physician. (Am Fam Physician 2001;64:1575-8.)

Hypodermoclysis is a method of infusing fluid into subcutaneous tissue that requires only minimal equipment. Technically, it is easier to administer fluids subcutaneously than intravenously. During the past two decades, many articles advocating this method have been published in the geriatric and palliative medical literature.(1,2) However, hypodermoclysis is suitable for use in many hospital and home-care situations regardless of the patient's age.(3) The advantages and disadvantages of this technique are presented in Table 1.


Advantages and Disadvantages of Hypodermoclysis


Low cost

More comfortable than IV administration

Less likely than IV administration to cause pulmonary edema or fluid overload

Simple insertion, less distressing than IV; easier reinsertion at new site

More suitable for home care than IV line, with less staff supervision and less need for hospitalization

Can be set up and administered by nurses in almost any setting

Does not cause thrombophlebitis

Has not been shown to cause septicemia or systemic infection

Can be started and stopped at any time by opening and closing the clamp on clysis tubing; no danger of clot formation


Usual rate only 1 mL per minute; only 3,000 mL (at two sites) can be given in 24 hours

Limitations on administration of electrolytes, nutrition additives and


Edema at infusion site is common

Possibility of local reactions

IV = intravenous.


A 1991 study(4) demonstrated the efficacy of fluid absorption in hypodermoclysis. Healthy elderly volunteers were infused with normal saline either intravenously or subcutaneously, using radioisotopic triated water and technetium pertechnetate. The infusion included 750 IU of hyaluronidase, and the saline infusion rate was 167 mL per hour. The absorption of fluid via the intravenous route was almost identical to that with the subcutaneous route in all subjects. Radioactivity could not be demonstrated at the subcutaneous site 75 minutes after completion of the infusion.

In an uncontrolled study,(5) hypodermoclysis was used in 36 instances in nursing-home residents with a mean age of 85 years and was associated with a return to clinical or functional baseline in 71 percent of subjects one week after the end of clysis. In a further study,(6) 60 patients (mean age: 80 years) with cognitive impairment who required parenteral fluids for at least 48 hours were randomly chosen to receive either intravenous or subcutaneous fluids. After adjusting for baseline differences, no differences in serum urea or creatinine levels were found between the two groups 48 hours later. The cost was much lower in the subcutaneous fluid group, and agitation related to the infusion was more prevalent in the intravenous fluid group.


Subcutaneous fluids are indicated for maintaining adequate hydration in patients who are unable to take adequate fluids orally, who are mildly to moderately dehydrated and in whom it is difficult or impractical to insert an intravenous line.(7) The main use of subcutaneous fluids has been in geriatric and palliative medicine settings.(1,5,6)

Oral hydration is often difficult in the presence of cognitive impairment, vomiting and nausea, infection, abdominal obstruction related to cancer, or cerebrovascular accident, especially in elderly patients.(1,8-10) Home use of intravenous infusion entails serious risks and requires close supervision by skilled medical staff. However, hospitalization is inconvenient for patients and families, and many patients wish to stay at home. The cost of hospitalization and the danger of nosocomial infections are further disadvantages of admitting a patient for hydration. Because of its safety and ease of administration, hypodermoclysis is a useful alternative to intravenous hydration.(11)

Terminal cancer patients usually stop eating and drinking near the end of life. The use of fluids in this situation is subject to debate, because nutrition and hydration have not been proved to prolong life or improve patients' well-being.(12,13) Several authors claim that hypodermoclysis (at a rate of 500 to 1,500 mL per 24 hours) circumvents many of the objections to other methods of hydration.(14,15) Clinical studies suggest that terminally ill patients with cancer may achieve adequate hydration with much lower fluid volumes than recommended for the average medical and surgical patient.(16) Also, patients and families can be disturbed by low fluid intake, particularly when there is active fluid loss from diarrhea, vomiting, bowel obstruction or profound sweating. In these situations the physician should discuss hypodermoclysis with the patient and/or caregivers.


There are few contraindications to hypodermoclysis. It should not be used when fluids must be administered rapidly and in large amounts, such as in patients with collapse, shock, severe electrolyte disturbance or major dehydration. It is also contraindicated when the patient may be at increased risk of pulmonary congestion or edema, such as severe congestive heart failure. Because of bleeding at the injection site, clotting disorders are another contraindication.



In ambulatory patients, hypodermoclysis sites include the abdomen, upper chest, above the breast, over an intercostal space and the scapular area. In

bedridden patients, preferred sites are the thighs, the abdomen and the outer aspect of the upper arm.(3,17) After one to four days, the needle and tubing should be changed, although infusion sets have been left in place for much longer periods without complications.(2) The reported duration of any one site in a palliative care unit was 4.7 days. Total hypodermoclysis duration was an average of 14 days.(14) In another study(18) using a Teflon cannula, the site duration was 11.9 [+ or -] 1.7 days versus 5.3 [+ or -] 0.5 days using a butterfly needle.


Fluid can be delivered subcutaneously by gravity at a rate of 1 mL per minute at one site; thus, about 1.5 L can be delivered at one site and 3 L at two separate sites over 24 hours.(2) In a prospective study(14) in a palliative care unit, 100 consecutive patients received an average volume of 1,203 [+ or -] 505 mL per day. One to 2 L can be given overnight to allow freedom from tubes during the day.(3) Another method involves administration of 500-mL boluses over one or two hours three times a day, with 150 U of hyaluronidase (Wydase) given at the subcutaneous site before the first morning infusion.(1)


The equipment consists of a solution bag, a tube with a drip chamber, a 21- or 23-gauge long-tube butterfly needle, povidone-iodine solution or alcohol skin preparation, and a sterile occlusive dressing.


Usually, normal saline (0.9 percent) is infused,(2,19) but 0.45 percent saline, one third saline with two thirds glucose 5 percent, or 5 percent glucose alone or with normal or half-normal saline have been administered in clinical practice.(1,2,5-7,19) Past reports warned of the danger of rapidly infusing electrolyte-free solutions such as 5 percent glucose. More recently, reports have been published on the use of 5 percent dextrose with no attendant risk.(7)

Hyaluronidase, an enzyme obtained from bull testes, has been used to enhance fluid absorption from subcutaneous tissue. Hyaluronidase temporarily lyses the normal interstitial barrier, which consists mainly of hyaluronic acid, a polysaccharide found in the intercellular ground substance of connective tissue.(1) Hyaluronidase decreases the viscosity of the connective tissue, thus increasing diffusion of the fluid administered subcutaneously for about 24 to 48 hours.(5)

When hyaluronidase is used to increase fluid absorption, one method of doing so is to add 150 U per L to a fluid infusion bag and to inject 75 U of hyaluronidase into each clysis site through the short latex tubing near the needle.(2) Some physicians have used 10 times this dose for hypodermoclysis by priming the needle and infusion set with hyaluronidase (1,500 U) and 1 to 2 mL of lidocaine.(3) Usually 150 U per L is an effective dose of hyaluronidase.(7) However, this dosage can cause discomfort and local reaction.(3) Many reports suggest that the addition of hyaluronidase is not necessary to prevent edema.(5,6,20-23) There are reports of the safe addition of 20 to 40 mmol of potassium chloride per L to the infused solution in cases where potassium replacement is needed (i.e., diarrhea, vomiting).(2,3,7,24)

No data have been reported on the absorption of morphine and other medications added to the fluid bag or given as a bolus, although concomitant subcutaneous infusion of such medications warrants investigation.

The technique for hypodermoclysis is summarized in Table 2.


Technique of Hypodermoclysis


1. Explain the procedure to the patient.

2. Select the infusion site.

3. Wash hands.


1. Assemble fluid and tubing. Prime line with selected fluid and hyaluronidase, using lidocaine if required.

2. Swab the site with povidone-iodine skin preparation solution using a circular motion, beginning at the center of the site. Allow at least one minute contact time. Do not touch prepared site again with fingers.

3. Insert needle, bevel up, into subcutaneous tissue at a 45- to 60-degree angle.

4. Secure needle and tubing with occlusive dressing.

5. Adjust fluid drip rate as prescribed.


1. Do not set drip rate to deliver more than 1 L in two hours.

2. Date and initial dressing; date and initial intravenous tubing.

3. Document infusion fluid on medication chart.

4. Check patient and infusion after one hour to ensure that the infusion site is correct, that there are no signs of edema, leakage, disconnection or fluid collection distal to the site, and that patient does not show signs of fluid overload.

5. If necessary, the infusion site can be massaged to enhance edema absorption.

Adverse Effects

The risks of hypodermoclysis are minimal when it is administered in conformity with accepted indications and guidelines. Adverse effects, which are rare and easily avoidable, depend mainly on the choice of solution, the volume and the infusion flow rate(7) (Table 3).

In a 1981 experiment,(21) 4,500 infusions of normal saline and 5 percent glucose solutions were administered to 634 patients, of whom the majority were older than 80 years. Few adverse effects were noted. The most common problem was fluid overloading, which caused either subcutaneous edema or heart failure in nine patients. Four of five patients with subcutaneous edema in the pelvic and genital regions rapidly responded to diuretics. Local infection occurred in only one patient, who developed cellulitis at the infusion site in the thigh. Two patients had ecchymoses, one of them with probable disseminated intravascular coagulation. The investigators concluded that hypodermoclysis is safe in older patients with mild to moderate dehydration.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.


(1.) Steiner N, Bruera E. Methods of hydration in palliative care patients. J Palliat Care 1998;14:6-13.

(2.) Berger EY. Nutrition by hypodermoclysis. J Am Ger Society 1984;32:199-203.

(3.) Farrand S, John Campbell A. Safe, simple subcutaneous fluid administration. Br J Hosp Med 1996; 55:690-2.

(4.) Lipschitz S, Campbell AJ, Roberts MS, Wanwimolruk S, McQuenn EG, McQueen M, et al. Subcutaneous fluid administration in elderly subjects. J Am Geriatr Soc 1991;39:6-9.

(5.) Hussain NA, Warshaw G. Utility of clysis for hydration in nursing home residents. J Am Geriatr Soc 1996;44:969-73.

(6.) O'Keeffe ST, Lavan JN. Subcutaneous fluids in elderly hospital patients with cognitive impairment. Gerontology 1996;42:36-9.

(7.) Ferry M, Dardaine V, Constans T. Subcutaneous infusion or hypodermoclysis: a practical approach. J Am Geriatr Soc 1999;47:93-5.

(8.) Challiner YC, Jarrett D, Hayward MJ, Al-Jubouri MA, Julious SA. A comparison of intravenous and subcutaneous hydration in elderly acute stroke patients. Postgrad Med J 1994;70:195-7.

(9.) Mansfield S, Monagham H, Hall J. Subcutaneous fluid administration and site maintenance. Nurs Stand 1998;13:56,59-62.

(10.) Freeman M. Subcutaneous fluid infusions. Aust Fam Physician 1991;20:1357.

(11.) Schen R. Administration of fluid by subcutaneous infusion. Harefuah 1997;132:716-7.

(12.) Dunlop RJ, Ellershaw JE, Baines MJ, et al. On withholding nutrition and hydration in the terminally ill. A reply. J Med Ethics 1995;21:141-3.

(13.) Waller A, Hershkowitz M, Adunsky A. The effect of intravenous fluid infusion on blood and urine parameters of hydration and on state of consciousness in terminal cancer patients. Am J Hospice Palliat Care 1994;11:622-7.

(14.) Fainsinger RL, MacEachern T, Miller MJ, Bruera E, Spachynski K, Kuehn N, et al. The use of hypodermoclysis for rehydration in terminally ill cancer patients. J Pain Sympt Manag 1994;9:298-302.

(15.) Fainsinger R, Bruera E. The management of dehydration in terminally ill patients. J Palliat Care 1994; 10:55-9.

(16.) Bruera E, Belzile M, Watanabe S, Fainsinger RL. Volume of hydration in terminal cancer patients. Support Care Cancer 1996;4:147-50.

(17.) Waller A, Carolin NL. Subcutaneous infusions. In: Waller A, Carolin NL, eds. Handbook of palliative care in cancer. Boston: Butterworth Heinemann, 1996:449-56.

(18.) Macmillan K, Bruera E, Kuehn N, Selmser P, Macmillan A. A prospective comparison study between a butterfly needle and a Teflon cannula for subcutaneous narcotic administration. J Pain Sympt Manag 1994;9(2):82-4.

(19.) Schen RJ, Singer-Edelstien M. Subcutaneous infusions in the elderly. J Am Geriatr Soc 1981;29:583-5.

(20.) Gluck SM. Hypodermoclysis revisited [Letter]. JAMA 1982;248:1310-1.

(21.) Schen RJ, Singer-Edelstein M. Hypodermoclysis [Letter]. JAMA 1983;250:1694.

(22.) Dasgupta M, Binns MA, Rochon PA. Subcutaneous fluid infusion in a long-term care setting. J Am Geriatr Soc 2000;48:795-9.

(23.) Bruera E, de Stoutz N, Fainsinger RL, Spachynski K, Suarez-Almazor M. Concentrations of hyaluronidase in patients receiving one hour infusions of hypodermoclysis. J Pain Sympt Manag 1995;10:505-9.

(24.) Schen RJ, Arielli S. Administration of potassium by subcutaneous infusion in elderly patients. BMJ 1982;285:1167-8.

MENAHEM SASSON, M.D., is a family physician in an urban clinic in Be'er Sheva, Israel, and assists in the home-care unit for terminal patients, also in Be'er Sheva. He is a lecturer and medical student clerkship coordinator in the Department of Family Medicine and Palliative Medicine at Ben-Gurion University of the Negev, Be'er Sheva, Israel.

PESACH SHVARTZMAN, M.D., is professor in the Department of Family Medicine and Palliative Medicine and chairman of the Division of Community Health at Ben-Gurion University of the Negev. He is also head of the Israeli Palliative Care Association.

Address correspondence to Pesach Shvartzman, M.D., Division of Community Health, Ben Gurion University of the Negev, P.O.Box 653, Be'er Sheva, 84105, Israel (e-mail: spesah@bgumail.bgu.ac.il). Reprints are not available from the authors.

COPYRIGHT 2001 American Academy of Family Physicians
COPYRIGHT 2001 Gale Group

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