RESEARCH DESIGN AND METHODSâ Fifty-one type I diabetic patients were ... Fifty percent survival rate of the first implanted catheter was 27 months (95%.
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and more specifically in the stability of insulin preparations to prevent immuno-inflammatory reactions and insulin amyloid deposits that appear to be involved in catheter failures.
Catheter Complications Associated With Implantable Systems for Peritoneal Insulin Delivery
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eritoneal insulin delivery has been investigated since the late 1970s as a means to improve the treatment of type I diabetes, especially in failures of multi-injection or continuous subcutaneous insulin infusion (1,2,3). The main conceptual advantage of the method is a more physiological prehepatic insulin delivery by absorption of insulin through ERIC RENARD, MD DOMINIQUE LAUTON, MD the portal circulation, resulting in imPIERRE BALDET, MD GUY COSTALAT, MD proved insulin bioavailability and lower MARIE-CHRISTINE PICOT, MD JACQUES BRINGER, MD peripheral insulinemia (4). The recent deDOMINIQUE JACQUES-APOSTOL, MD CLAUDE JAFFIOL, MD velopment of implantable systems for continuous peritoneal insulin infusion OBJECTIVE — To evaluate catheter survival and identify mechanisms involved in catheter (CPU) has reduced the discomfort of preobstructions during a 109.8 patient-year experience with implanted pumps for peritoneal insuviously used external portable pumps lin delivery. that were connected to implanted peritoRESEARCH D E S I G N A N D M E T H O D S — Fifty-one type I diabetic patients were neal catheters (5,6,7,8). However, pilot recruited in feasibility studies of two models of implanted systems for peritoneal insulin delivery. Both systems had a silicone-coated polyethylene catheter and infused Hoechst 21 PH neutral studies performed to investigate the feasiinsulin (U400 or U100). Catheter obstruction was suspected each time the increase of insulin bility of CPU from these devices indicated flow rate over 50% of usual need was insufficient to correct an impairment of glycemic control in the absence of intercurrent factors. A laparoscopic examination was then systematically that the peritoneal catheter remained the performed under general anesthesia. The disclosed material occluding the catheter was submit- weakest link of the infusion system (5,8). ted to a pathological analysis. By actuarial analysis, we examined the estimated effects of the Thus, the incidence of catheter obstrucpotential determinants of the catheters' durations of proper operation on catheter survival. tions has been reported between 13 and R E S U L T S — Over an implantation duration of 25.8 ± 14.0 months (mean ± SD), 34 58 per 100 patient-years (5,6,7,8,9). The catheter obstructions were diagnosed in 24 patients, resulting in an incidence of 31 events per 100 patient-years. Fifty percent survival rate of the first implanted catheter was 27 months (95% two main identified causes of catheter confidence interval [CI]: 19-32) on actuarial analysis. Six catheters were cleared under laparos- blockages were the formation of a fibrin copy and 24 were replaced, while 2 systems were definitively explanted and 2 combined re- clot at the peritoneal tip and the developplacements of pump and catheter were performed because of an associated pump slowdown. In five cases, an alkaline rinse procedure of the pump was necessary after catheter replacement to ment of omental encapsulations around restore usual insulin needs, suggesting an associated insulin aggregation in the pump. Twenty the peritoneal part of the catheter, but the obstructions were due to a fibrin clot at the catheter tip, and 14 obstructions were created by a mechanisms responsible for these events tissue encapsulation around the catheter. A previous experience of peritoneal insulin infusion from portable pumps or a longer duration of diabetes (>21 years) both appeared as conditions remained elusive (5,6,7,8). We report significantly reducing the time of a catheter's proper operation (P < 0.01 and P < 0.05, here a survival analysis of peritoneal cathrespectively) either by tip obstructions or by encapsulations. Pathological analysis of catheter encapsulations showed a collagen fibrosis in all studied patients (n = 11), which was associated eters established from the results of a diwith a lymphocytic infiltrate in five patients and also with anti-insulin immunoreactive amyloid agnostic procedure for catheter obstrucdeposits in four patients. Catheter tip clots were composed of fibrinlike material, nonreactive to tions using systematic laparoscopy anti-insulin antibodies. during a 109.8-patient-year experience of C O N C L U S I O N S — Catheter obstruction is a frequent adverse technical event occurring CPU from implanted pumps and our with implanted insulin pumps. Progress is expected in the biocompatibility of catheter material search for factors affecting the catheters' time of operation, including a pathological analysis of the material collected from obstructed catheters.
An analysis of frequency, predisposing factors, and obstructing materials
From the Departments of F.ndocrinology, Pathology (P.B.), and Medical Information (M.-C.P.), Lapeyronie Hospital, Montpellier, France. Address correspondence and reprint requests to Eric Renard, MD, Department of Endocrinology, Lapeyronie Hospital, 34295 Montpellier Cedex 5, France. Received for publication 1 August 1994 and accepted in revised form 27 October 1994. CI, confidence interval; CPU, continuous peritoneal insulin infusion.
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RESEARCH MATERIALS A N D M E T H O D S — Fifty-one type I diabetic patients (30 men, 21 women),
DIABETES CARE, VOLUME 18, NUMBER 3, MARCH 1995
Renard and Associates
with low C-peptide levels, were recruited in our clinic from January 1990 to February 1994 in feasibility studies of CPU from implanted systems. Subjects had a diabetes history of 21.0 ± 9.4 years and were 41.5 ± 11.2 years old at implantation time (means ± SD). Twenty-seven were previously treated by continuous subcutaneous insulin infusion and 24 were previously treated by CPU from portable pumps. Implanted systems Two models of programmable implantable infusion systems were alternatively implanted after the approval of our institution's ethical committee and the obtaining of an individual written consent. Forty-six patients were initially treated by the Minimed Implantable Pump model 2001 (Minimed Technologies, Sylmar, CA) and five by the Model 1000 implantable pump from Infusaid (Norwood, MA). The characteristics of these devices have been described in detail elsewhere (6,7). The catheters of both implantable pumps are made of polyethylene and are silicone coated. The insulin infused by both pumps is Hoechst 21 PH neutral semisynthetic human insulin (Hoechst, Frankfurt, Germany), stabilized by a glycol-polyethylene polypropylene surface active agent (Genapol) (10). The concentration of insulin is 400 U/ml (U400) in Minimed devices and 100 U/ml (U100) in Infusaid devices. Implantation procedure has been described in detail elsewhere (8). Briefly, the pump was placed in the right or left lower quadrant of the abdomen in a subcutaneous pocket created by the surgeon under general anesthesia. The catheter was surgically implanted into the peritoneal cavity. While the catheter was attached to the abdominal wall by a specifically designed flange, its peritoneal part was left free in the peritoneal cavity. Cumulated experience with implanted systems was 109.8 patient-years and individual duration of implantation was 25.8 ± 14.0 months (range: 2-51) in April 1994. Definitive removals of im-
DIABKTES CARE, VOLUME 18,
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plants were necessary in nine incidents because of unexpected complications (recurrent catheter obstructions in one case, skin erosions in seven cases) or severe intercurrent illness (in one case). Pump replacements were performed because of an expected battery failure after 3 years in 11 cases and because of adverse events in 9 cases (a slowing of the infusion flow from the pump in 6 cases; skin erosion, premature battery failure, and electronic defect, respectively, in the 3 other cases). Diagnostic procedure of catheter obstructions Catheter obstructions were suspected when an impairment of blood glucose control, occurring either progressively or suddenly, could not be corrected by a 50% increase of usually required insulin while in the absence of intercurrent factors. Diabetic ketoacidosis occurred in two instances. In each case of blockage suspicion, a laparoscopy was performed under general anesthesia. The diagnosis of catheter obstruction was confirmed by the identification of an occluding material in the lumen or around the tip of the catheter and the absence of insulin flow from the catheter tip when an insulin bolus was ordered under laparoscopic examination. It was further confirmed that the lack of insulin delivered was due to catheter blockage by a verification of the insulin flow from the pump before the catheter replacement or by the restoration of insulin flow from the catheter tip after laparoscopic clearance of obstruction of the catheter. Both pump and catheter replacements were performed in two incidents of combined defects identified during this procedure. Pathological analysis of occluding material Occluding material located inside the lumen or around the tip of the catheter was immediately extruded or scraped and collected in a solution (10 ml 40% formaldehyde, 10 ml acetic acid, 10 ml methanol, 40 ml distilled water). Samples were em-
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bedded in paraffin for pathological and immunohistochemical studies. Sections 3-5 /im thick were stained by hematoxylin-eosin for standard examination, Masson's trichrome for collagen study, and Sirius red for the detection of amyloid deposits. Immunohistochemical reaction was performed with anti-insulin antibodies from Immunotech E2E3 clone and avidin-biotine-peroxydase complex. Survival analysis and statistical method Results are expressed as means ± SD (or SE if specified). The survival rate of catheters was studied by Kaplan-Meier method (product-limit), which provides actuarial estimates of catheter survival probability (11). Survival time was defined as the time elapsed from the date of catheter implantation until obstruction or withdrawal because of device cxplantation (maximal expected time is 36 months) or for data analysis. We examined the effects of each potential determinant of catheter lifetime on survival after relations between prognostic factors were searched using chi-squared analysis or Fisher's exact test if chi-squared analysis was not valid. Differences in survival patterns between groups were evaluated using the log-rank test. The statistical software SAS version 6.08 (PROC LIFETEST) was used for statistical analysis. RESULTS Incidence of catheter obstructions During our 109.8 patient-year experience, 34 episodes of catheter blockages were diagnosed in 24 patients using the laparoscopic procedure described in METHODS. Thus, catheter obstructions occurred in 47% of the patients and showed an incidence of 31/100 patient-years. Five patients presented one recurrence, one patient a double recurrence, and one patient a triple recurrence. In 20 cases, the nature of catheter obstruction was a white, clot-like material inside the lumen of the catheter peritoneal tip a few milli
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Catheter complications in CPU pumps
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SE) months, and actuarial analysis showed a 50% survival rate of first catheters of 27 months (95% CI: 19-32). As shown in Fig. 1A, 89% of catheters were expected to be working effectively after 1 year, 67% after 18 months, 53% after 2 years, and 31% after 36 months. The survival rate of the second catheter, implanted after a first episode of obstruction, was 69% after 1 year and 57% after 18 months (Fig. IB). Operating time of the second catheter was thus 16.5 ± 1.8 (mean ± SE) months but was not significantly different from the first catheter on paired analysis. The incidence of catheter blockages was lower with Minimed than with Infusaid systems: 29.2 and 40.2/100 patient-years, respectively. Thus, tip clots tended to be more frequent with Infusaid than with Minimed devices (28.7 vs. 16.2/100 patient-years).
Management of catheter obstructions The permeability of six encapsulated catheters was restored by clearing the catheters with forceps under laparoscopy. Twenty-four catheters had to be replaced, mostly because of clots at the tip of the catheter (in 19 cases) or because of adherent unresectable encapsulations (in 5 casFigure 1—Actuarial analysis of the survival es). We decided on a definitive explantation rate of peritoneal catheters (means ± SE). Surof the system because of a simultaneous invival analysis offirst implanted catheters (A) and tercurrent illness (ovarian cancer) in one of second implanted catheters (B). case of encapsulation and a double recurrence of catheter blockage over 9 months in another case. Both pump and catheter meters long, and in 14 cases, it was a tis- were replaced in two patients presenting sue encapsulation around the peritoneal catheter encapsulations because the meapart of the catheter. Respective incidences surement of the pump outflow was draof "clots" and encapsulations were thus matically reduced without any indication 18 and 12.7/100 patient-years. Four pa- of electronic defect and was interpreted as tients experienced both types of obstruc- massive insulin aggregation in the pump. Infivecases, insulin requirements tions at different times. Two additional remained unusually high after the cathepartial catheter obstructions by tip clots ter replacement and could be normalized were disclosed when systems were reonly after an alkaline rinse procedure of placed for expected battery failure after 3 the pump using 0.01 mol/1 NaOH. The years, although insulin delivery rate did resolution of the insufficient pump delivnot increase over 20% of usual needs. ery after this alkaline rinse strongly sugOperating life of the first imgested that insulin aggregates were displanted catheter was 23.5 ± 1 . 4 (mean ±
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Figure 2—Actuarial analysis of catheter survival according to previous route of insulin delivery before implantation. , patients under previous peritoneal infusion; , patients under previous subcutaneous infusion (P
