Short-duration peripherally inserted central catheters do not alter viscoelastic parameters in healthy dogs

Abstract

Objective

To determine if short-duration peripherally inserted central catheters (PICCs) cause a hypercoagulable state in healthy dogs, based on point-of-care viscoelastic coagulation monitor (VCM).

Animals

Ten beagle dogs were randomly and equally allocated into control and PICC groups.

Procedure

Control dogs had VCM analysis on whole blood following direct venipuncture before sedation (T0) and 2 h after sedation (T2). In the experimental group, a PICC was placed (medial saphenous or femoral vein) under sedation and removed after 4 h, with measurements before placement (T0) and 2 and 6 h after placement (T2 and T6, respectively). Parametric data were analyzed using 1-way ANOVA with Holm-Šídák test for multiple comparisons and paired or unpaired Student’s t-test. Nonparametric data were analyzed using Friedman test with Dunn multiple comparison test for Wilcoxon matched-pairs signed-rank test, and Mann-Whitney U test for PICC group, control group, and to compare PICC versus control groups, respectively.

Results

Clot formation time was longer at T2 versus T6 (P = 0.0342, but not clinically relevant) in the PICC group, with no significant differences between the PICC and control groups.

Conclusion and clinical relevance

Short-term placement of a PICC line did not alter viscoelastic endpoints in healthy beagles.

Peripherally inserted central catheters (PICCs) are commonly used in critically ill humans and animals for frequent blood sampling or injections, but can cause catheter-related thrombosis (CRT) (1–3). There are 3 main types of CRT: a fibrin sheath around the catheter, an occluded catheter lumen, or a thrombus on endothelium adjacent to the catheter (3), with the latter potentially causing life-threatening thromboembolic events. In humans, most CRT are asymptomatic (4), with incidence rates of 0 to 20% in symptomatic individuals or up to 90% in patients with a central venous catheter (CVC) (5). In humans, PICCs have a higher risk of deep vein thrombosis compared to CVCs, especially in malignancy or critical conditions (2). In addition, CVC can induce a local hypercoagulable state due to disrupted vascular endothelium, reduced blood flow, or a thrombogenic catheter (6). Development of a systemic hypercoagulable state as determined by thromboelastography (TEG) occurred as early as 1 h after CVC or PICC placement in critically ill humans and healthy pigs (7), whereas there was a significant hastening of initial fibrin formation (R time) with indwelling pulmonary arterial catheters in humans (8). Conversely, in healthy dogs, jugular CVC for ≤ 72 h did not appear to develop a hypercoagulable state based on TEG (9).

In critically ill animals, PICCs are often used to prevent extravasation of irritating solutions and facilitate frequent, short-term venous sampling. In addition, many ill dogs have procoagulable comorbidities, including immune-mediated hemolytic anemia, protein-losing nephropathy, pancreatitis, sepsis, hyperadrenocorticism, neoplasia, or no spleen (10,11). Our objective was to determine whether placement of a short-term PICC promoted development of a hypercoagulable state in healthy dogs as determined using a point-of-care viscoelastic coagulation monitor (VCM) device. We hypothesized that PICC placement in healthy beagle dogs promotes development of a systemic hypercoagulable state when compared to placement in control beagles.

This study was reviewed and approved by the University of Calgary Institutional Animal Care and Use Committee (AC21-0172). Power analysis using expected differences in mean TEG endpoints for maximum amplitude with α = 0.05 and a desired power of 0.8, based on a coagulability study involving PICC insertion in humans and swine, indicated a minimum of 4 per group. Ten adult beagle dogs, apparently healthy based on history, physical examination, and recent bloodwork (CBC and biochemistry panel within 2 mo), were enrolled and assigned (using a random number generator: https://www.calculatorsoup.com/calculators/statistics/random-number-generator.php) to either the control or PICC groups. Fur over the lateral saphenous, medial saphenous, and femoral veins was clipped after anesthetic cream (EMLA cream; AstraZeneca, Cambridge, UK) was applied ≥ 20 min before the first venipuncture or PICC insertion. A baseline peripheral venous blood sample (0.4 to 1.0 mL) was collected by venipuncture from the lateral saphenous vein for VCM analysis (T0). Dogs were sedated with butorphanol (Torbugesic; Zoetis, Kalamazoo, Michigan, USA), 0.2 mg/kg and dexmedetomidine (Dexdomitor; Zoetis), 5 μg/kg, intramuscularly. At ~20 min later, dogs in the PICC group had an 8-inch, 22-gauge Intracath PICC (Argon Medical Devices, Plano, Texas, USA) inserted into the medial saphenous or femoral vein using aseptic technique (maximum of 3 attempts). Immediately after placement, the catheter was flushed with 3 mL of 0.9% sodium chloride (1). At 1 h after PICC insertion or sedation, all dogs received atipamezole (Antisedan; Zoetis), 0.05 mg/kg, intramuscularly. All dogs had a second venipuncture sample collected from the contralateral lateral saphenous vein 2 h after sedation (T2). In the PICC group, 4 h after sedation administration, 0.4 mL of blood was drawn directly from the PICC (T4), using the 3-syringe technique, with the PICC removed thereafter (1). The final blood sample was collected 2 h after PICC removal (6 h after insertion) by lateral saphenous venipuncture (T6) (Figure 1).

FIGURE 1.

Schematic depiction of study methods and time points for viscoelastic analysis.

PICC — Peripherally inserted central catheter.

Immediately after collection, whole blood was analyzed using the VCM device (Entegrion, Durham, North Carolina, USA), following manufacturer’s instructions. Clot time (CT), clot formation time (CFT), alpha angle (α), maximum clot formation (MCF), amplitude at 10 (A10) and 20 (A20) min post-CT, and lysis index at 30 (LI30) and 45 (LI45) min post-MCF, and a visual graph of analyses were recorded and analyzed using reference intervals (12).

Data were tested for normality using a Shapiro-Wilk test. Descriptive statistics included mean with SD for parametric data and median with interquartile range (IQR) for nonparametric data. The VCM parameters for the PICC group at T0, T2, T4, and T6 were analyzed with 1-way ANOVA with Holm-Šídák multiple comparison test for parametric data, and with Friedman test with Dunn multiple comparison test for nonparametric data. In the control group, VCM parameters were compared between T0 and T2 using a paired Student’s t-test for parametric data and Wilcoxon matched-pairs signed-rank test for nonparametric data. To determine differences between control and PICC groups for physical examination findings and VCM data, unpaired Student’s t-test and Mann-Whitney U test were used for parametric and nonparametric data, respectively (P < 0.05). All analyses were done using Graph Pad software (Prism v.9, 4.0 for Mac; GraphPad Software, San Diego, California, USA).

Vital parameters are shown in Table 1. Seven male and 3 female dogs were enrolled (no significant differences between sexes). One PICC placement required 2 attempts. Sample T4 from the PICC group was excluded from the final analysis as 2 samples could not be analyzed (catheter port failure and blood clotting).

TABLE 1.

Vital parameters for dogs in control and peripherally inserted central catheter (PICC) groups.

	Control	PICC	P-value
Body weight (kg), median (IQR)	12.3 (2.5)	12 (2.4)	0.7302
Rectal temperature (°C), mean (SD)	38.3 (± 0.3)	38.7 (± 0.24)	0.0835
Heart rate (bpm), mean (SD)	102 (± 25.45)	88 (± 12.47)	0.0744
Respiratory rate (brpm), median (IQR)	24 (6)	24 (5)	0.6429

bpm — Beats per minute; brpm — Breaths per minute.

Body weight and respiratory rate were not normally distributed and are presented as median and IQR, whereas rectal temperature and heart rate were normally distributed and presented as mean ± SD.

Relative to manufacturer’s reference intervals, 1 control dog had shortened CT, A10, A20, and MCF at T0, and a shortened MCF at T2; and another control dog had lengthened CT, CFT, and MCF at T2. All control mean VCM endpoints were within reference intervals, with no significant differences between T0 and T2 (Table 2). One dog in the PICC group had a lengthened CFT and shortened α, A10, A20, and MCF at T2 compared to reference intervals, but all remaining endpoints for this sample were within reference intervals. Within the PICC group, there was a significant, albeit not clinically relevant, difference, with a longer CFT at T2 (median: 207 s, IQR: 103) compared to T6 (median: 178 s, IQR: 65 (P = 0.0342) (Table 2). There were no significant differences between control and PICC groups (Table 2).

TABLE 2.

Viscoelastic coagulation monitor (VCM) vet parameters for control (T0, T2) and peripherally inserted central catheter (PICC) groups (T0, T2, T6), with units and reference values (12).

Parameter (units) and reference Interval	T0		P-value control vs PICC	T2		P-value control vs PICC	T6		P-value control T0 vs PICC T6	P-value control T2 vs PICC T6
	Control	PICC		Control	PICC		Control	PICC
Clot time (seconds) 241 to 470	334 (± 108)	366 (± 38.5)	0.5513	397 (± 49.1)	376 (± 45.3)	0.4942	—	424 (± 22.2)	0.1052	0.2983
Clot formation time (seconds) 104 to 266	216 (± 32.5)	202 (± 31.7)	0.5162	220 (± 36.5)	207 (103) a	0.8413	—	199 (± 35.6) a	0.4587	0.3846
Alpha angle (degree) 43 to 64	51.1 (± 2.39)	52.7 (± 3.06)	0.3739	51.5 (3.97)	50.2 (8.4)	0.4524	—	53.0 (± 3.62)	0.3669	0.4127
Amplitude 10 (VCM units) 16 to 30	18.8 (± 2.46)	20.5 (± 2.54)	0.3739	18.4 (± 1.95)	18.7 (± 3.21)	0.8615	—	20.7 (± 2.98)	0.3085	0.1907
Amplitude 20 (VCM units) 22 to 38	24.8 (± 3.28)	27.0 (± 2.88)	0.3079	24.6 (± 2.20)	25.3 (± 3.69)	0.7169	—	27.2 (± 3.45)	0.2924	0.1906
Maximum clot formation (VCM units) 29 to 44	31.8 (± 4.31)	33.7 (± 2.42)	0.4023	35.2 (± 6.96)	34.8 (5)	0.6905	—	34.1 (± 3.20)	0.3672	0.74922
Lysis index 30 (%) 98 to 100	100 (0)	100 (0)	> 0.999	100 (0)	100 (0)	> 0.999	—	100 (0)	> 0.999	> 0.9999
Lysis index 45 (%) 98 to 100	100 (0)	100 (± 0.02)	> 0.999	100 (± 0.02)	100 (0)	0.1667	—	100 (0)	0.4048	0.8254

^aDifference within the PICC group: T2 versus T6 (P = 0.0342).

There was no evidence that short-term placement of PICCs promoted development of a systemic hypercoagulable state in healthy beagle dogs as measured by VCM. Development of a systemic hypercoagulable state occurred secondary to CVC in humans and swine (7), and may predispose to CRT formation, a known complication in humans and dogs with CVC placement (2,10). However, the Critical Care Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines do not identify placement of PICCs or CVCs as a specific risk factor for a hypercoagulable state in dogs (11), consistent with the current results and those of another study reporting no alterations of viscoelastic endpoints in healthy dogs with CVCs ≤ 72 h (9). This is important when managing critically ill patients with comorbidities that could increase risk of thrombus formation. Dogs may be less likely to develop a hypercoagulable state secondary to catheter placement compared to humans and pigs, given the physiologic differences among their hemostatic systems (13). Dogs have greater fibrinolytic activity that may contribute to a decreased tendency to develop a localized or systemic hypercoagulable state (13).

Our power calculation was based on changes in TEG parameters in swine and humans after CVC line insertion (7); however, based on species differences in hemostasis, a larger sample size would have been appropriate. As development of thrombi in human children occurred within 1 to 4 wk after PICC insertion, PICC indwelling times > 4 h may increase the likelihood of developing a procoagulable state (4). Studies evaluating longer PICC indwelling times are required. Although TEG or rotational thromboelastometry (ROTEM) are considered the gold standard for hemostatic viscoelastic testing in veterinary medicine (14), they are typically done at referral laboratories. In human medicine, the current reference standard for identification of CRT relies on TEG or ROTEM with concurrent ultrasonographic imaging of the vasculature (4). In this study, although we used a validated point-of-care viscoelastic testing device to detect a hypercoagulable state, paired TEG or ROTEM comparative analyses with VCM measurements would have been ideal (12).

Compared to CVCs, PICCs are linked with an elevated risk of deep vein thrombosis in humans (2). Placement of an intravenous catheter activates the contact pathway via the intrinsic pathway, contributing to thrombus formation. Fibroblastic sheathing may occur as fibronectin adheres to foreign material in vessels, attracting macrophages that differentiate into smooth muscle cells and fibroblasts, producing collagen and enveloping the catheter and combining with other foreign material to form a connective tissue sheath (2,3). This process begins within hours in swine (8). One dog in the PICC group had an intracatheter thrombosis and intra-syringe blood clotting 4 h after PICC insertion (T4) that precluded T4 sampling. However, no VCM data in this dog at T2 (prolonged CFT, decreased a angle, A10, A20, and MCF) or T6 (all within the reference range) supported a hypercoagulable state. Therefore, we attributed intracatheter clotting to local thrombus formation rather than a systemic hypercoagulable state. Increased risk of venous thrombosis in pediatric humans has been associated with a catheter-to-vein diameter ratio > 0.33, and with a PICC insertion site more proximal compared to a mid-arm location (5). In adult humans, a catheter-to-vein ratio of < 0.45 is recommended to decrease the risk of PICC-induced thrombosis (3). The ratio of vein diameter to catheter size has not been evaluated in small animals but could be considered in future studies.

Last, catheter materials differ in thrombogenicity. The current study used PICCs of Vialon biomaterial, which is similar to polyurethane and reportedly less thrombotic than Teflon (polytetrafluoroethylene), but there were no differences in rates of phlebitis or thrombosis for short-duration PICC (15). In human medicine, silicone catheters are more frequently used than polyurethane catheters and may be less thrombogenic (15). Future studies could explore the effects of various catheter materials on viscoelastic parameters.

This study had additional limitations, including missing data from PICC complications and the absence of baseline bloodwork on the study day. Dogs were assumed to be systemically healthy based on history, recent bloodwork, and physical examination; however, underlying subclinical coagulopathies, which may have contributed to insignificant hemostatic changes, could not be entirely ruled out.

In conclusion, we detected no clinically significant effects on systemic hemostasis with short-term (4 h) PICC placement evaluated using point-of-care viscoelastic parameters in healthy beagles. Additional studies are required to determine whether the current results apply to sick and hospitalized animals, other breeds, different catheter types, concurrent drug administration, and longer-duration PICC placement.