Contrast media extravasation injury: a prospective observational cohort study

With the rapid development of multi-detector computed tomography, there are approximately 76 million examinations in the world each year, of which 50% of patients need to use contrast media (CM) intravenously [1], which is on the increase. CM are mainly used for qualitative and differential diagnosis of pathological changes based on the absorption difference between normal and diseased tissues; however, they need to be injected into the human body through the vein with instantaneous high pressure and a rapid method. In addition to its special physical and chemical properties (such as high concentration, high osmotic pressure, and high viscosity), various complications can occur after injection, of which CM extravasation is the main complication [2], with an incidence rate of 0.1‒1.2% [3‐10]. The diagnosis of CM extravasation is mainly based on a comprehensive clinical judgment of the time and symptoms of extravasation [11, 12].

Some studies have shown that extravasation causes pain, swelling, blisters, secondary wound infection, tissue adhesion, and even serious consequences such as compartment syndrome and amputation [13‐15], which increase the patient's pain, prolong the hospital stay, increase medical costs, and affect the patient's disease diagnosis, treatment, and rescue, ultimately affecting the patient's quality of life.

To reduce the incidence of CM extravasation, many research teams have made significant efforts, but due to high-pressure injection and the physicochemical properties of CM drugs, patient age, underlying diseases, and other reasons, CM extravasation is difficult to completely avoid [16]. When CM extravasation cannot be avoided, we hope to take some measures to minimize the harm caused by extravasation. Through a literature review, we found that there have been few studies on the damage caused by CM extravasation, and some studies have been reported in the form of individual cases. Some studies have mentioned the grading of extravasation damage, but there is a lack of continuous follow-up after extravasation. There are also studies that cannot further analyze and discuss moderate and severe CM extravasation due to insufficient sample size.

Therefore, this study aims to analyze the risk factors for moderate and severe injuries caused by CM extravasation by following up on cases of CM extravasation in the radiology departments of three hospitals over a period of 5 years. Taking preventive measures in advance to reduce extravasation damage for patients who may be at high risk of extravasation is needed to avoid serious harm caused by extravasation.

Studies have shown that the mechanisms of different degrees of injury caused by CM extravasation mainly include the following: 1. cytotoxicity: in vitro studies have shown that CM can cause morphological degeneration of human umbilical vein endothelial cells [22] and induce apoptosis of endothelial cells [23]. 2. Mechanical compression: the degree of mechanical compression is directly related to the amount of extravasation. High-dose CM extravasation can cause severe rupture of external venous tissues, especially when high-pressure injections and injection sites are difficult to monitor [4]. 3. Osmosis: hyperosmolar CM extravasated in the subcutaneous tissue increases local tissue osmotic pressure. The dehydration of the vascular endothelial cell network causes local platelet aggregation, which causes inflammatory changes by increasing capillary permeability, leukocyte infiltration, and releasing other inflammatory chemokines, such as prostaglandin E1 and E2 [5].

Analysis of registered data across the United States by Dykes et al. showed that mild, moderate, and severe incidences of injuries caused by CM extravasation were 94.6%, 4.7%, and 0.8%, respectively [2]. In contrast, we had no cases of severe injury; instead, potentially deteriorating cases were controlled at the moderate injury stage. This may be related to the CM-type selection of the three hospitals in the study. Since the development of CM, they have gone through a development process from ionic to non-ionic, from high-osmolality to low-osmolality to isotonic: (1) high-osmolality CM have osmotic pressures as high as 5–7 times that of plasma; Due to the relatively high number of adverse reactions, it is currently rarely used; (2) low-osmolality CM are named after their significantly reduced osmotic pressure compared to ionic high-osmolality CM. They include two types: non-ionic monomers and ionic dimers, with osmotic pressure twice that of plasma; (3) after further reducing the osmotic pressure of the low permeability CM, an isotonic contrast agent was developed, but due to its current high price, it has not been widely used.

The CM used in the radiology departments of the three hospitals was the non-ionic type, which is the dominant type with less necrosis, edema, and hemorrhage compared with ionic CM [12]. In the classification of non-ionic CM, we found that the use of iohexol for injection is one of the risk factors for moderate CM injury. The osmotic pressure of iohexol is 830 mOsm/kg H₂O, which is higher than those of iodixanol (290 mOsm/kg H₂O) and ioversol (710 mOsm/kg H₂O). Plasma osmotic pressure is composed of oncotic pressure (macromolecular blood proteins), and crystal osmotic pressure is composed of inorganic salts, glucose, and other small molecules. The normal value is 280–310 mOsm/kg H₂O, and blood proteins generally cannot penetrate the capillary wall; therefore, although the plasma oncotic pressure is low, it plays an important role in the water balance inside and outside the blood vessels. Once the hypertonic fluid is extravasated, the plasma osmotic pressure and tissue osmotic pressure gradually increase, and patients are more likely to experience local skin redness, pain, damage, necrosis, dehydrated vascular endothelial cells, local platelet aggregation, leukocyte infiltration, and inflammatory damage. In addition, the higher viscosity (11.4 mPa∙s) and lower hydrophilicity (the octanol water partition coefficient: 708) of iohexol may result in more severe damage than ioversol and iodixanol.

Because massive extravasation leads to a mechanical compression effect [24, 25], the amount of extravasation is directly proportional to the damage caused by extravasation [2, 7, 10, 23, 24], and our research also confirms this. To reduce the amount of CM leakage, we suggest that during the high-pressure injection of CM, the nurse closely observes the patient's reaction and changes in the pressure curve on the high-pressure display screen through the intercom and video system in the observation window. If the pressure line suddenly increases or exceeds the pressure value of 250 psi (1 psi = 6.895 kPa), the injection of CM should be stopped immediately. The patient should be asked through the intercom to see if there is swelling at the injection site, and measures should be taken promptly for symptomatic treatment. It is recommended to use an extravasation detection accessory (EDA) to assist in monitoring the occurrence of CM extravasation. The main principle of EDA is to use abnormal soft tissue at the insertion site to signal the operator to stop injection when CM extravasation occurs, and automatically terminate injection before a large amount of extravasation occurs. In recent years, various leakage monitoring and alarm technologies have developed rapidly. The research results of Dykes et al. [2] showed that the incidence and total amount of CM extravasation in patients who used extravasation monitoring were significantly lower than those who did not use it (P < 0.05).

Tumors are also risk factors for moderate extravasation injuries. Some studies have shown that chemotherapy status does not affect the incidence of drug extravasation [26]. However, it may stimulate the veins and make them more vulnerable to subsequent treatment [27]. In addition, the disease state of patients with tumors and the decline of immunity after chemotherapy caused the body to react more heavily after drug extravasation, and the injury was more difficult to heal. With the development of medicine, most patients with tumors undergoing chemotherapy have been implanted with a central venous catheter, including the CVC, PICC, and Port. We recommend that patients with high-pressure injections choose high-pressure resistant central venous catheters at the beginning. In our study, we were surprised to find out that patients with high-pressure-resistant central venous catheters did not have CM extravasation. High-pressure resistant central venous catheters are usually rated at 300 psi with flow rates up to 10 mL/s [28], which can meet the speed and pressure requirements of intravenous contrast-enhanced CT.

The degree of CM extravasation injury is also related to the injection site of the peripheral short catheter [18]. Compared with the loose subcutaneous layer, the involvement of the tight subfascial compartment causes more injury [29]. Therefore, extravasation injury usually indicates worse consequences at the injection site with a thinner subcutaneous plane, such as the back of the hand and wrist [25], which is consistent with the 13.491 (p = 0.001) times of moderate extravasation in the back of the hand compared with the high-pressure injection in the forearm and elbow fossa in this study. Therefore, we suggest that when CM is injected intravenously through a peripheral venous catheter, the catheter should be preferentially placed in the venous with thick, straight, and good elasticity at the cubital fossa, including the median cubital vein, cephalic vein, and basilic vein, and should be avoided from puncturing at the hands, wrists, feet, and ankles as much as possible. If the vein at the elbow fossa is not suitable for puncture, the forearm vein can be chosen. Meanwhile, avoid repeated punctures of the same vein.

Our study prospectively collected information on patients with CM extravasation. The results provide a reference for reducing the degree of injury after CM extravasation. Our findings support early risk assessment for patients requiring angiography and the selection of high-pressure-resistant central venous catheters for patients with malignant tumors. To take effective measures to reduce CM extravasation, patients at high risk of extravasation support should avoid back-of-the-hand injections and iohexol to reduce moderate and severe CM extravasation injuries.