Portable infusion pumps in ambulatory cancer chemotherapy

Portable Infusion Pumps in Ambulatory Cancer Chemotherapy

TERRY PLASSE, MD, TAKAO OHNUMA, MD, PHD, HOWARD BRUCKNER, MD, KAREN CHAMBERLAIN, BSN, TERRY MASS, BSN, AND JAMES F. HOLLAND, MD

Fifty-seven adult patients receiving chemotherapy were treated with a total of 133 infusions using portable user-worn infusion pumps, the Autosyringe AS*2F, Cormed ML6-4, and two earlier versions of the latter, the Sigmamotor ML6-2 and ML6-3. Ninety-eight infusions were given on an ambulatory basis. Fourteen infusions were given through peripheral venous catheters, 115 through central venous catheters, and four intra-arterially. Of 127 evaluable infusions, 65 were completed within 5% and 87 within 10% of the planned rate; results are similar for both inpatient and outpatient infusions. The Cormed ML6-4 pump was equal to the Autosyringe AS*2F in reliability but superior to the latter in patient preference. There were no instances of dangerously rapid administration of the drug. The only serious catheter complications were a pneumothorax after insertion of a subclavian catheter in one patient and cellulitis in a leukopenic patient with a Broviac catheter. All but three patients preferred outpatient therapy to hospitalization. Outpatient therapy costs about $300 per day less than in-hospital treatment.

Cancer 50:27-31, 1982.

LINICAL TRIALS frequently call for administration C of chemotherapeutic agents by continuous infusion for several days. These treatments are usually given in the hospital because intravenous therapy is generally considered to be impractical at Ihome. Many of the patients, however, are not in need of hospitalization except for drug administration. Treatment of such patients where pharmacologic studies involving frequent blood samplings are not being done could be better accom- plished on an outpatient basis. Patients are not sepa- rated from their families; those who are working can continue to do so, and the costs of treatment can be greatly reduced by eliminating hospitalization.

Following is a report on our experience in giving continuous infusion chemotherapy using user-worn min- iature infusion pumps, mostly on an outpatient basis.

Materials and Methods

Patient Selection

During the period from February 1979-through De- cember 1980, the authors treated 57 adult patients who

From the Department of Neoplastic Dliseases, Mt. Sinai School of

Supported in part by USPHS Research Grant CA-15936. Address for reprints: Terry Plasse, MD, Department of Neoplastic

Diseases, Mt. Sinai School of Medicine, One Gustave L. Levy Place, New York NY 10029.

The authors wish to acknowledge the assistance of Mrs. N. Fried- man in collecting and tabulating this da1.a.

Accepted for publication May 4, 1981.

Medicine, New York, New York.

received a total of 133 infusions using patient-worn portable infusion pumps (Table 1). All patients were to receive infusions lasting at least 24 hours. Patients treated were on protocols calling for infusions of 5-flu- orouracil (5-FU) (20-30 mg/kg-d, n = 62), bleomycin (7.5 mg/m2-d, n = 33), vinblastine (1.5-2.25 mg/m2- d, n = 15), methylgloyxal bis-guanylhydrazone (methyl- G) (500-800 mg/m2-d, n = 13) or methotrexate ( 150 mg/m2-d, n = 9) either alone or in combination with other drugs. In one case, a saline infusion was used to maintain patency of an arterial line. Initially, inpatients were treated using the pumps to test the machines’ per- formance under close observation; subsequently inpatient treatments were structured to teach the patients how to use the pumps and for staff to observe their changing of the drug reservoir and compliance with instructions prior to outpatient infusions.

Patients received outpatient infusions if they were not in need of hospitalization for reasons other than administration of medication. The patient and/or at least one family member had to be able to change the drug reservoir and to detect malfunction of the equipment. Patients who could not reach Mt. Sinai Hospital within one half-hour had to have local physicians who could take care of emergency situations.

Study Procedure

Temporary catheters (Subclavian Intrafusor, Sor- enson Research Co., Salt Lake City, Utah, or Drum

0008-543X/82/070l/0027 $0.75 0 American Cancer Society

27

CANCER July 1 1982

I A U L t I . Infusions Administered

Vol. 50

Pump used

Autosyringe Cormed Sigmamotor Sigmamotor ML6-4 ML6-2 ML6-3 Total

- AS*2F

Number of patients 29 20 12 15 57* Male 17 6 4 8 27* Female 12 14 8 7 30*

Number of infusions 45 49 18 24 133" Inpatient IS 3 5 3 29 Out patient 26 43 13 I9 98" Inpatient/outpatient$ 1 3 0 2 6

Number of days 159 192 51 75 477 Inpatient 55 18 17 10 I00 Outoatient 104 174 34 65 371 -

* Actual number of patients entered; some used more than one

t Actual number of infusions given; some used more than one pump pump.

Cartridge Catheter, Abbott Laboratories, Northwest Chicago, Illinois) were inserted in the out-patient office for ambulatory patients. All patients, both hospitalized and ambulatory, had chest x-rays after insertion of subclavian catheters. Broviac catheters were inserted in the operating room under local anesthesia, in most instances on an outpatient basis. Two of the intra-arterial catheters were inserted percutaneously and two were inserted at the time of laparotomy. When temporary venous catheters were used, the pump was usually set up by a physician (T.P.), but infusions through Broviac catheters were managed by nurses (K.C. and T.M.). The pumps used were one Sigmamotor ML6-2 and one Sigmamotor ML6-3 peristaltic pumps; 4 Cormed ML6- 4 peristaltic pumps (Cormed, Inc., Middleport, NY) (a successor model to the Sigmamotor) and 3 Auto- syringe AS*2F syringe-type pumps (Autosyringe, Inc., Hooksett, NH) (Table 2). The Autosyringe pumps were connected to the vascular access catheters, both venous and arterial, with arterial pressure tubing (Sorenson Research Co., Salt Lake City, Utah). The drug reservoirs for the Cormed and Sigmamotor pumps have tubing attached; on occasions when an extension was needed, arterial tubing was used. The amount of drug in the reservoir and the time at the beginning and end of each infusion was recorded by the nurse or physician caring for the patients. When infusion was completed

serially to complete an infusion. $ Infusion started in hospital and finished at home after discharge.

at home, the time was noted by the patient or a family member. Patients were instructed to bring in the used syringes and drug reservoir bags for determination of residual volume by a nurse or physician. Becton-Dick- inson disposable plastic syringes of 20-50 ml volume were used as drug reservoirs for the Autosyringe pumps. Disposable flexible plastic drug reservoirs supplied by the manufacturer were used in the Sigmamotor and Cormed pumps. The drugs were measured before and after infusion using Becton-Dickinson disposable plastic syringes of 10-50 ml volume. (Becton-Dickinson syringes are accurate to +5%.) The rate delivered in percentage was calculated as shown below:

Percentage delivered Volume delivered f time in which delivered

Volume planned t time planned x 100

The time is measured from the start to finish of infusion and includes periods of complete cessation of flow when this occurred.

- -.

Results

A summary of location of administration of infusions and total time of infusions is given in Table 1. The mean durations of infusions were 3.5 and 3.9 days, respectively, for the Autosyringe and Cormed pumps, and 2.8

TABLE 2. Infusion Pump Characteristics - .-

Max. time/ Max. vol./ Rate Pump Type Weight (g) Size (cm) filling filling ml/d

.____

Autosyringe AS*2F Syringe 482 6.4 X 18.3 X 7.3 49.5 hrs 44 ml 10-21 1 2 Sigmamotor ML6-2 Peristaltic 508 8.1 X 12.2 X 6.0 5 days 50 ml 12-19 Sigmamotor ML6-3 Peristaltic 316 8.1 X 12.2 X 6.0 3 days 70 ml 20-35 Cormed ML6-4 Peristaltic 420 8.1 X 12.2 X 4.1 5 days 50 rnl 10-50 __

No. 1 PORTABLE INFUSION PUMP - Plasse et al. 29

TABLE 3. Routes of Administration - Autosyringe Cormed Sigmamotor Sigmamotor

AS*2F ML6-4 ML6-2 ML6-3 Total

Subclavian 5 2 5 5 16* Antecubital 17 0 3 9 29 Broviac 14 44 6 7 70* Peripheral vein 5 3 4 3 14* Intra-arterial 4 0 0 0 4

* Actual number of patients entered; one used two pumps 10 complete an infusion.

and 2.1 days, respectively, for the Sigmamotor ML6- 2 and ML6-3 models. Table 3 gives the routes of administration used. In three cases, two pumps were used sequentially for an infusion. Peripheral veins were used primarily on outpatients receiving 24-hour infusions of methotrexate or methyl-G. There was one infiltration near the end of an infusion of methyl-G without any adverse sequelae. Three patients received three-day bleomycin infusions via peripheral veins; all three were inpatients and in all cases their intravenous lines infil- trated and had to be restarted several times during the course of treatment. Three of the 5-FU infusions were given via hepatic artery; the rest were intravenous.

Figure 1 shows the percentage of infusions delivered within 5% or 10% of the planned rate. Delivery of the infusions within 5% of the planned rate was considered excellent and is as close as we can measure with the equipment used; delivery within 10% of the planned rate was considered adequate. The reliability of the Auto- syringe and Cormed pumps wa:; quite similar.

Initially, we had some mechanical problems with the Cormed pump. In one, a faulty bearing caused erratic, slow drug administration. In another, improper wiring caused it not to pump at all, though the meter registered the appropriate rate. Of the first 12 infusions, only 42% were within k1070 of the planned rate; of the next 12 infusions, 75% were within -tlO% of the 24 infusions from 6/80 through 12/80, 93% were within f10% of the planned rate. Data were not recorded for one infusion. No such trend was seen for the Autosyringe pumps.

Table 4 gives the causes, where apparent, for failure to complete infusions within 10% of the planned rate. I n two-thirds of the cases in which the rate was outside the +I070 range, the cause was not apparent. Several problems most likely account lor these failures. The Autosyringe has no way to measure battery charge. Although the battery is designed to run the pump for fivs days between charges, in several instances the unit slowed down while the patient was still using it. Re- charging the battery one or two nights during an infusion alleviated the problem. The other major problem which might account for many of the failures is improper placement of the syringe plunger in the machine.

I f the plunger is not perfectly parallel with the syringe barrel, after part of the medication has been infused, the drive mechanism disengages without setting off the alarm. I n some instances, having the patient change to a new syringe allowed for completion of the rest of an infusion on schedule. We could not attribute any problems to the pulsatile, rather than continuous, mode of fluid administration by the Autosyringe.

The battery charge can be checked directly on the Cormed and appears to hold for at least five days, though we routinely have patients change the battery on day 3 of a five-day infusion.

Catheter complications were uncommon and not usually serious (Table 5 ) . The subcutaneous leakage of the Broviac catheter was of methyl-G and did not produce any local irritation. Pneumothorax occurred on the third placement of a subclavian catheter in a patient receiving vinblastine infusions and who had had two previous insertions without incident. Placement of a Broviac catheter had been refused by the patient. After several days

within 10% of planned rate

w i t h i n 5 % " " "

patient patient patient patient

AUTOSYRINGE CORMED SIGMAMOTOR SIGMAMOTOR A S E F M L 6 - 4 M L 6 - 2 ML6-3

FIG. I . Reliability: percent of infusions delivered within 5% or 10% of planned rate. The bar on the left represents all infusions for a particular pump, on the right those infusions given only on an outpatient basis. The shaded area of each bar represents the percentage of infusions administered within 5% of the planned rate. The whole bar represents the percentage of infusions administered within 10% of the planned rate.

30 CANCER July I 1982 Vol. 50

TABLE 4. Causes of Failure to Deliver Infusion Within f10% of Planned Rate

Problem Autosyringe Cormed Sigmamotor Sigmamotor

AS2F ML6-4 ML6-2 ML6-3 Total

Improper setting 0 0 Improper reservoir placement 3 0 Tubing occlusion within pump 0 1 Tubing occlusion outside pump 1 0 Catheter pulled out O* 0 Battery failure 0 2 Defective bearing 0 2 Uncertain 8 9

Total infusions outside k of planned rate 12 14 Total infusions with accuracy data for pump 41 48

* Catheter pulled out on one addition infusion for which amount infused was not recorded.

1 0 0 0 0 0 0 2 3

17

of chest tube drainage, the pneumothorax resolved and the patient was continued for several months on vinblastine via Broviac catheter, which she then accepted. The only other hospitalization for catheter complication was for cellulitis at the cutaneous end of a Broviac catheter while the patient was leukopenic after a 5-FU infusion. This resolved with systemic antibiotics without removal of the catheter. The episodes of phlebitis were mild and required only warm soaks for several days. Two accidental removals of antecubital catheters occurred at home; one patient did so while working on his boat. Afterwards, all antecubital and subclavian catheters were sutured in place. The one accidental subclavian catheter removal occurred in an inpatient whose catheter had been sutured in place. In no case was there any serious bleeding or other problems related to the catheter removal.

A comparison of costs for standard inpatient versus ambulatory treatment, based on charges at the Mt. Sinai Hospital in the summer of 1979, is given in Table 6 . The costs given are the amount billed to the patient or insurer and include physician fees, laboratory and x-ray costs, operating room time for Broviac catheter insertions, medications, equipment and hospitalization. Outpatient treatment saves about $300 per day, the difference being attributed primarily to the saving in daily room charges. Most major insurance carriers rec- ognize the advantage of outpatient treatment and have paid for outpatient infusions with only small deducti- bles.

TABLE 5. Catheter Complications

Comolication

Phlebitis Leak from cracked catheter head Subcutaneous leakage Cellulitis a t catheter insertion

site, after 5 months Pneumothorax Catheter pulled out accidentally

Route

Ant ecu bit al Antecubital Broviac

Broviac Subclavian Antecubital Subclavian

~- Occurrences

3 1 I

I I 2 I

1 2 0 3 1 2 0 1 1 I * 1 3 0 2 7 26

1 1 40 21 127

Discussion

Administration of certain agents by continuous infusion is theoretically better than bolus injections. Drugs which are phase or cycle specific, such as 5-FU, vinblastine and bleomycin, might be more effective when continuous steady-state levels are maintained. Continuous infusion of 5-FU changes the dose-limiting toxicity from myelosuppression to mucositis, allowing concomitant administration of myelosuppressive agents at higher doses.’ Vinblastine when given by five-day infusion has been active in breast cancer in some patients who were refractory to bolus ~inblastine.’.~ Bleo- mycin has been shown in an experimental model to cause less pulmonary toxicity and have greater therapeutic efficacy when administered as a continuous infusion rather than in bolus form.’

Protocol trials using infusions lasting more than 8- 12 hours have traditionally required hospitalization, though many patients on such protocols are ambulatory and not in need of hospitalization other than for administration of medication. Treating these patients on an ambulatory basis enables them to carry on more nearly normal lives and decreases the attendant costs of hospitalization. In comparing the results of standard inpatient infusion therapy with our outpatient experience, the accuracy of inpatient infusion rates must be considered. Most of our patients receiving 5-FU and bleomycin infusions in the hospital are treated on gen- eral medical or surgical floors. While it has not been possible to quantify the variation in flow rate and the breaks in treatment, variations do occur, even with the use of pole-mounted infusion pumps, and there are oc- casional delays in therapy when catheters infiltrate.

Against this background, while delivery reliability of the pumps tested has not been ideal, results appear similar to those on our inpatients treated by standard drug administration techniques even with pole-mounted infusion pumps. We initially noted better reliability with the Autosyringe than the Cormed pump.6 As we have accumulated more data, however, our results with the Cormed have improved to the point where the reliability

No. 1 PORTABLE INFUSION PUMP . Plasse et al. 31

TABLE 6. Cost Per Course of Treatment ~

Outpatient with

treatments Outpatient Outpatient with broviac broviac, subsequent

Inpatient temporary catheter catheter 1st treatment

5-day 5-FU* $226 I $ 746 12-day B-CMFt 4312 1266

$1494 1831

$614 906

* 5-day continuous infusion, 5-FU. t Bleomycin continuous infusion, days 1-4 and 8-1 I , cyclophos-

phamide, methotrexate and 5-FU bolus, days 5 and 12.

of both pumps is similar. The Autosyringe pump is eas- ier to observe for malfunction, but problems do occur. The Cormed pump is much smaller than the Autosy- ringe and most patients prefer it because it fits easily under clothing and is unlikely to snag on garments; there are no controls outside the housing. In no case, with any pump, did we have a very high rate of infusion which could adversely affect a patient. A major problem with the Cormed pump may have been nonuniformity of the tubing going through the peristaltic mechanism. In June, 1980, steps were taken by the manufacturer to improve the standardization of the tubing within and between lots. We noted an improvement in the accuracy of delivery from July 1980, after our previous stock of drug reservoirs had been used.

Dorr et al.’ studied nine patients who received a total of 23 four-day infusions using the Ar/med infusion pump. They noted a need for frequent recalibration of the pumps during each course of therapy but were able to complete most of the infusions within 10% of the desired period. Their peripheral venous catheters per- formed satisfactorily for an average of two days. All catheter replacements and rate adjustments were made at the hospital.

Tamborlane and colleagues used the Autosyringe AS*2C infusion pump, which has a mechanism for de- livering bolus doses in addition to a steady low-flow infusion, to administer insulin subcutaneously to diabetes in an inpatient* and subsequently outpatients’ setting. All patients, seven in each study, achieved much better control of their diabetes with continuous infusion insulin therapy, supplemented with small preprandial boluses, than they had with conventional bolus injections. There were no clinically dangerous episodes of hyper- or hypoglycemia, and no mechanical failures in 11 10 days of outpatient pump use. No data are provided on accuracy of insulin infusion rates but the equipment functioned well enough to provide a therapeutic benefit in an outpatient setting.

Infusion chemotherapy, using the Autosyringe and Cormed pumps, is feasible on an outpatient basis in selected patients. Complications are infrequent. Both types of pumps tested, the Autosyringe and Cormed, are equally reliable. As we have gained more experience with this equipment, the accuracy of delivery of drugs has improved but variations in the rate of drug delivery have remained the major problem.

For infusions lasting more than 24 hours, central venous access is essential as peripheral intravenous lines quickly infiltrate in active patients. We have found the Broviac catheters to be extremely useful and reliable not only for infusion therapy but for bolus drug administration and for drawing blood on patients with poor veins. The use of arterial rather than venous con- necting tubing prevents blood from backing up into the lines and clotting. Infusions can be set up and monitored by nurses once central lines are inserted.

Attention to quality control is essential for use of these pumps. Minor details such as angulation of the plunger in the Autosyringe pump can cause major changes in drug delivery. We expect that as our experience increases with both the Autosyringe and Cormed pumps, which function well within &5% accuracy on bench testing, the reliability of medication delivery will improve. Outpatient infusion therapy of- fers patients who are on protocols involving infusions an opportunity to carry on more normal lives and spend more time with their families, as well as providing a major cost benefit compared to inpatient treatment.

REFERENCES

1. Riella MC, Schreiber BN. Five years experience with a right atrial catheter for prolonged parenteral nutrition at home. Surg Cy- necol Obster 1976; 143:205-208.

2. Lu K, Yap HY, Watts S, Loo TL. Comparative clinical phar- macology of vinblastine (VLB) in patients with advanced breast cancer. Proc Am Assoc Cancer Res ASCO 1979; 20:271.

3. Bruckner H. Unpublished observations. 4. Yap HY, Blumenschein GR, Hortobagyi G, Tashima C, Loo

TL. Continuous 5-day infusion of vinblastine (VLB) in the treatment of refractory advanced breast cancer. Proc Am Assoc Cancer Res ASCO 1979; 20:334.

5. Sikic BI, Collins JM, Mimnaugh EG, Graham TE. Improved therapeutic index of bleomycin when administered by continuous infusion in mice. Cancer Treat Rep 1978; 62:2011-2017.

6. Plasse T, Ohnuma T, Bruckner H , Cohen S M , Holland JF. Ambulatory chemotherapy using portable infusion pumps. Pror A m Assoc Cancer Res ASCO 1980; 21:316.

7. Dorr RT, Trinca CE, Griffith K, Dombrowsky PL, Salmon SE. Limitations of a portable infusion pump in ambulatory patients receiving continuous infusions of anticancer drugs. Cancer Treat Rep 1979; 63:211-213.

8. Tamborlane WV, Sherwin RS, Genel M. Felig P. Reduction to normal of plasma glucose in juvenile diabetes by subcutaneous administration of insulin with a portable infusion pump. N Engl J Med

9. Tamborlane WV, Sherman RS, Genel M, Felig P. Out-patient treatment of juvenile onset diabetes with a preprogrammed portable subcutaneous insulin infusion system. Am J Med 1980; 68:190-196.

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Portable infusion pumps in ambulatory cancer chemotherapy