Analyzing outcomes for peripheral versus central administration of vasopressors: A narrative review

Abstract

There is an emerging body of evidence to suggest that the peripheral administration of vasopressors is safe and effective in many clinical contexts and often superior to central administration. Vasopressors are a class of medications used to create vasoconstriction in patients with shock to increase systemic arterial blood pressure and tissue perfusion. Certain clinical circumstances require the use of these vasoactive drugs immediately for which the need to administer these drugs peripherally becomes paramount, although controversial. The authors present a narrative review dedicated to describing the current practice of the route of administration of vasopressors, comparing peripheral versus central administration, and explaining the advantages and drawbacks of each route as well as potential complications associated with them.

Introduction

Vasopressors are a class of medications used to create vasoconstriction in patients with shock to increase systemic arterial blood pressure and tissue perfusion.[1] Typically, the route of administration of these agents is through a central venous catheter, regardless of the patient’s location in the hospital (i.e., intensive care units, operating rooms, resuscitation bays), largely to avoid complications associated with its administration like local skin necrosis, limb necrosis, compartment syndrome, and so forth.[2]

Certain clinical circumstances require the use of these vasoactive drugs immediately for which the need to administer these drugs peripherally becomes paramount, although controversial. The route of administration of these agents, whether central or peripheral, has been a topic of considerable debate and investigation in clinical practice, especially over the past decade and since the beginning of the COVID-19 pandemic, in which lesser patient interaction to minimize exposure was preferred.[3,4,5]

This narrative review aims to provide a comprehensive comparison between central and peripheral administration of vasopressor agents, as well as provide a perspective of the existing literature, clinical outcomes, and practical considerations comparing the route of vasopressor administration.

Advantages of central administration of vasopressors

A central venous catheter (CVC) is an invasive line that has been placed into a large bore central vein (i.e., internal jugular, subclavian vein, iliac vein, or common femoral vein).[6] Central venous access is obtained by percutaneous puncture to cannulate the desired vein, often using ultrasound guidance and the Seldinger technique to complete the catheterization.[6] CVC placement is employed in the management of multiple patients for hemodynamic monitoring, and medication and fluid administration.[7] Several vasopressors including but not limited to norepinephrine, epinephrine, vasopressin, and dopamine are commonly administered via CVC, often simultaneously.[1]

Common indications for administration of vasopressor drugs through CVC include pre-existing central venous access, lack of reliable peripheral intravenous (PIV) access due to certain clinical conditions (e.g., edema, deep venous thrombosis, cellulitis, burns, or inability to obtain a PIV), requirement of multiple vasopressor agents, use of nonstandard vasopressor concentration or requirement for higher than maximal allowable peripheral dose, and anticipated duration of vasopressor infusion exceeding 24 hours.[8]

Central administration of vasopressors may be especially convenient for patients requiring longer hospital stays as the treatments of many other conditions commonly require CVC placement for appropriate therapies.[6] Other procedures requiring CVC access include the placement of vena cava filters, venous angioplasty stents/balloons, pulmonary artery catheters, and cardiac pacemakers.[9]

Safety and outcomes of central administration of vasopressors

Intravenous vasopressors are primarily delivered via central venous access, given concern for extravasation and tissue injury associated with peripheral administration.[10] In the United States, over 5 million CVCs are inserted annually for various reasons including intravenous access and resuscitation. These devices, however, are not free of complications.[11] A recent study examining CVC placement in adults found that up to 2.1% of patients experienced mechanical complications such as pneumothorax requiring intervention,[12] 0.5–1.4% experienced symptomatic deep-vein thrombosis directly attributable to the CVC,[12] and another 0.5–1.4% experienced bloodstream infection.[12] Current estimates are similar, if not higher, among pediatric patients.[13] Central venous access complications significantly increase the length of hospital stay and healthcare costs and negatively impact patients’ quality of life.[14]

When considering the complications of vasopressor administration via CVC, one must acknowledge the inherent risks of CVC placement in general. More than 15% of patients receiving a central venous catheter undergo complications of some kind, with arterial puncture, hematoma, and pneumothorax being the most common.[15] The severity of these complications is wide-ranging. Notable potential complications include the following:

Inadvertent arterial puncture

Even with ultrasound guidance, arteries may accidentally be punctured instead of the targeted vein. Arterial puncture is estimated to occur in 3.7 to 12% of all central venous access procedures.[16] It can lead to increased morbidity and mortality if not promptly recognized.[17] This is particularly worrisome in cases where the subclavian artery is punctured as its anatomical location does not allow it to be easily compressed.[16] Overall, treatment by CVC removal and mechanical compression is successful in only 5.6% of cases and is generally considered a poor management method.[17] Treatment via endovascular methods or open surgical repair has a much higher rate of success at 94.6% and 100%, respectively.[17]

Venous thrombosis

Indwelling CVCs have been known to contribute to the formation of catheter-related thrombosis.[18] Due to their size, femoral vein thrombi caused by venous catheters have the most significant potential to embolize.[19] To add to this issue, the majority of patients with a CVC in the femoral vein who develop deep venous thrombosis (DVT) have no clinical symptoms, which may lead to a false sense of security among clinicians and makes knowledge of the risk of this complication more important.[19] Data suggest that a catheter-related DVT may occur at any time, and no “safe” period for catheterization exists.[19] Critically ill patients have a high risk of developing venous thromboses, which may occur despite chemical prophylaxis.[20] Sequelae of these venous thrombosis in the setting of CVC can be serious and include peripheral limb edema as well as acute limb ischemia. As such, all ICU patients with CVC should be considered high-risk and receive chemical prophylaxis.[21]

Catheter-related infections

Central line-associated bloodstream infections (CLABSIs) have been shown to increase hospital costs and patients’ length of stay.[11] CLABSIs carry a mortality rate of 12%–15%.[22] The most commonly reported causative pathogens of these bloodstream infections are coagulase-negative staphylococci, Staphylococcus aureus, enterococcus species, and Candida species.[23]

When central venous access is required, strict sterile protocols should be observed. The Centers for Disease Control and Prevention (CDC) has instituted guidelines for the prevention of CLABSIs, which include education regarding the insertion and maintenance of intravascular catheters, weighing risks and benefits of CVC placement, the preferential use of ultrasound to aid in CVC placement, and the prompt removal of any intravascular catheter that is no longer essential.[11] Investigations do not support routine catheter removal and replacement on a scheduled basis.[24] The type of catheter material used also matters, with polytetrafluoroethylene or polyurethane catheters having been associated with fewer infectious complications than catheters made of polyvinyl chloride or polyethylene.[25]

The CDC recommends using a subclavian site rather than a jugular or a femoral site for central line placement in adult patients to minimize infection risk.[26] The literature, however, is conflicted on this topic with some studies supporting a higher risk of CLABSI at the femoral site and lower risk at subclavian and jugular sites,[27] while others report no difference in infection risk.[12,28] The femoral vein should be avoided when possible due to the higher risk of CLABSIs associated with this site.[11]

In addition to these general risks associated with CVC placement, central administration of vasopressors has been associated with the following complications:

Local tissue injury

Skin necrosis and gangrene have been associated with long-term central vasopressor administration via CVC and are likely related to the extravasation of vasopressor medication to the area immediately surrounding the CVC insertion site.[29] One study noted that such instances of local tissue injury began after an average infusion duration of 55 hours and occurred at multiple CVC sites.[30] Reducing the overall time a CVC is in place has been associated with a decreased frequency of local tissue injury.[31] Data suggest that the overall occurrence of complications with central administration of vasopressors via CVC is low, although when tissue injuries do occur, they tend to be severe.[32] One study found that out of 325 reported events of tissue injury caused by vasopressor extravasation, only seven events were from administration via CVC, with the rest coming from peripherally administered vasopressors.[10]

Distal ischemic tissue injury

Ischemic skin lesions are a severe complication among ICU patients. Occurrences of distal ischemic tissue injury have been reported as adverse events related to widespread vasoconstriction in patients receiving high doses of vasopressor medications such as norepinephrine, epinephrine, and dopamine.[33,34,35] Peripheral ischemia may deteriorate to gangrene, the treatment of which necessitates surgical debridement and potential amputation of ischemic limbs.[36] Common sites of ischemic tissue injury include the distal extremities (fingers, toes, etc.), tongue, and trunk of the body.[37]

Advantages of peripheral administration of vasopressors

Peripheral venous cannulation is among the most commonly performed medical procedures. It allows for the infusion of hydration fluids, blood products, nutritional supplements, and a myriad of medications such as vasoactive drugs.[38] In general, peripheral catheters are preferred when IV access is required for shorter periods, when direct access to the central circulation is unnecessary, and when smaller gauge catheters suffice for the indicated treatment.[38]

Peripheral IV (PIV) access is generally easier to obtain and less uncomfortable for patients when compared to CVC. In emergent situations, strategic use of peripheral vasopressor administration to quickly control and stabilize patients may facilitate the eventual placement of a CVC[10] and reduce the time to commencement of vasopressor and antimicrobial administration.[39] In such cases, restoring mean arterial pressure quickly is prioritized over the risk of tissue injury from vasopressor extravasation. Current clinical guidelines recommend peripherally administered vasopressors rather than waiting for central venous access in patients with septic shock.[40]

Multiple studies have found that vasopressors administered via PIV result in a 2.5-hour reduction in time to initiation of medications.[8] Yerke et al.[41] found that implementing a protocol for peripheral administration of norepinephrine safely was able to avoid 1 CVC day in the average patient, with the majority of included patients not requiring CVC insertion at all; no patient experienced significant ischemic tissue injury with the protocol used.

Safety and outcomes of peripheral administration of vasopressors

Extravasation may be defined as the escape of a vesicant drug into the extravascular space and represents a significant risk that must be considered when administering vasopressors via PIV.[42] The drug can enter the extravascular space by leaking from the point where the catheter enters the vessel, from a point where the catheter has punctured through a vein, or from a dislodged PIV that inadvertently leaks vasopressors in the interstitial space.[2] Many drugs, including vasopressors, may be harmful when directly exposed to tissues and have the potential to cause severe tissue damage with lasting injury.[2]

The apprehension of peripheral administration of vasopressors originated from various case reports in the 1950s and 1960s, describing norepinephrine extravasation from a peripheral venous catheter.[43,44,45] In these case reports, vasopressor extravasation led to superficial tissue injury, limb ischemia, myofascial necrosis, compartment syndrome, and the hemodynamic sequelae of abrupt cessation of vasopressor delivery.[44] In current clinical practice, however, the risk of local adverse events associated with PIV insertion is relatively low when compared to the rates of potentially more serious complications associated with CVC insertion and maintenance.[46]

Several systematic reviews have suggested that the risk of adverse PIV events ranges from 1.8 to 7% in adults and is 3.3% in children.[2,46,47] When adverse events do occur, they tend to be minor and are usually able to be managed medically without the need for surgical intervention, including extravasation, cellulitis, and thrombophlebitis.[2,46] Major adverse events, such as skin ischemia or necrosis, are typically rare.[48] Several studies have shown that hospitals that follow a specific safety protocol for peripheral vasopressor administration have a lower incidence of complications.[2,49] In particular, studies have described lower complication rates when using protocols that include PIV site inspections by hospital staff every 1–2 hours, supporting the need for widespread protocolized monitoring of PIVs running vasoactive medications.[47] Current clinical guidelines recommend starting peripheral vasopressors via PIV before eventually placing a CVC in shock patients.[40]

Site of PIV catheter placement

Several factors must be considered when deciding on a location for PIV placement, including local venous anatomy. Higher frequencies of extravasation are reported in areas with smaller veins or slower circulation such as the antecubital fossa of the wrist or the saphenous vein of the ankle.[43,45] Larger veins tend to be less injury-prone as they provide adequate dilution of the administered vasopressor and are less likely to spasm.[50]

Several studies have demonstrated safety with PIV location in the arm proximal to the wrist.[51,52] PIV vasopressors given proximal to or in the antecubital fossa are unlikely to cause local tissue injury, especially if for a short duration (6 hours or less).[10] While still considered to be generally safe, a PIV inserted into a patient’s hand or wrist is associated with an increased risk of adverse events due to these veins being smaller and/or more fragile (Marsh 2021).[53] Ultimately, the clinician placing the PIV must use their better judgment to weigh the advantages and risks of proximal versus distal PIV placement.

General contraindications for PIV placement include, but are not limited to:

• Sites over joints (except in trauma situations), due to increased risk of catheter kinking or dislodgement.[54]

• Sites on the dominant upper extremity, out of concern for patient comfort and increased risk of dislodgement.[54]

• The presence of an arteriovenous fistula in the extremity, as the introduction of a catheter may disrupt venous blood flow or damage the fistula.[55]

• The presence of infected tissue, due to the risk of introducing a systemic infection.[56]

• Evidence of sclerosis or phlebitis, which may indicate damage to venous integrity and suggest an increased risk of extravasation.[57]

• A site where catheter placement was recently attempted, particularly if a hematoma formed following the prior attempt.[58]

Gauge of PIV catheter

A variety of IV-gauge sizes have historically been utilized for peripheral IV vasopressor administration, ranging from 14G to 24G.[10] A meta-analysis of 1835 patients found fewer complications associated with 20-gauge or larger catheters, suggesting that the use of larger catheters should be preferred in clinical contexts.[2] Attempts have been made to establish a protocol for the size and placement of PIVs used for vasopressor administration. One rigorous peripheral vasopressor protocol includes the following guidelines: (1) that the vein be >4 mm in diameter measured with ultrasonography, (2) the use of a catheter with an IV gauge larger than 20G, (3) ultrasonographic confirmation of placement, and (4) no IVs be placed in the hand or wrist (Cardenas-Garcia et al.).[59]

Complications of peripheral administration of vasopressors

Peripheral intravenous catheters (PIVs) are the most commonly used invasive medical device in health care, with an overall failure rate of 35–50%.[60] Regardless of which fluid or medication is being administered, PIV placement comes with several inherent risks, including phlebitis, bruising, hematoma formation, and cellulitis.[61] Thrombophlebitis occurs in up to 15% of patients who receive PIV catheters.[62] Successful PIV catheter placement requires skill, and the first-time success rate for PIV placement ranges from 65 to 85%.[38] Factors associated with unsuccessful PIV catheter placement and maintenance are not well understood[38] but may include unique patient factors, clinician experience level, or specific properties of the medical device being used. The risk of adverse events seems to be higher in female and elderly patients.[61]

Extravasation events are a significant concern with PIV vasopressor administration as they are a major cause of iatrogenic morbidity in hospitalized patients.[49] Mechanical contributions to extravasation injuries with PIV catheter placement largely involve faulty cannulation technique or a patient’s physiologic predisposition to infiltration injury. Cannulation practices known to contribute to extravasation injury include inadvertent puncture of a vein proximal to the site of injury, use of unstable catheters, use of a catheter larger than the vein size, use of a site near joint flexion, and catheter malfunction.[49] Potential sequelae of faulty cannulation may include compartment syndrome, where the extravasation of fluid or medications results in the elevation of intracompartmental pressures, leading to ischemic damage to tissue.[63] Immediate treatment of acute compartment syndrome includes relief of compartment pressure via fasciotomy to restore tissue perfusion.[64] Perhaps the most important aspect of the management of acute compartment syndrome is to maintain a high index of suspicion among at-risk patients. Frequent serial limb examinations are recommended in such patients.[65]

The medicinal properties of vasopressors present an added risk when extravasated from patients’ venous systems. Direct alpha-adrenergic-mediated vasospasm of the smaller veins and the vasa vasorum leads to inadequate distal blood flow. Subsequent increases in the hydrostatic pressure of the venous circulation cause further effusion of the vasopressor into the tissue. Ischemia then follows parallel to the infusion site as the vasopressor diffuses into tissue space and the tributary veins constrict.

As venous inflammation occurs, backflow commences into the arteriolar capillaries due to hydrostatic pressure.[45] The resulting inadequate blood flow can lead to local hypoperfusion, causing tissue injury and necrosis.[66] The site of vasopressor infiltration typically manifests with blanching, swelling, hypoperfusion, and local hypothermia, followed by purple discoloration and extreme pain. Within 48 hours, fluid-filled bullae or vesicles may form, leading to skin epithelialization, tissue sloughing, eschar formation, or gangrene.[49]

Treatment of extravasation events

If extravasation occurs, prompt recognition and timely, appropriate treatment may prevent further tissue injury, pain, or even limb loss. Upon recognition, the peripheral venous catheter should be aspirated while it is removed and phentolamine (5–10 mg in 10–20 mL normal saline) injected subcutaneously around the extravasation area to antagonize local alpha-adrenergic effects. If phentolamine is unavailable, 2% topical nitroglycerin ointment or subcutaneous terbutaline may also be considered.[49] Other known treatment methods include warm compresses and elevation of the affected limb. Cold compresses, hyaluronidase monotherapy, and conivaptan should be avoided.[49]

Vasopressor extravasation progressing to necrosis has been linked to high morbidity. Debridement and excision of necrotic tissue should be considered. Surgical flushing with normal saline is often used for severe hyperosmolar extravasations. Assessment and surgical decompression of compartment syndrome may be necessary in certain cases of extravasation.[49]

The exact identity of the extravasated vasopressor may require variations in treatment:

Norepinephrine

The most commonly reported vasopressor extravasation agent in the literature is norepinephrine.[50,67] Its predominant effects are on the alpha-1 adrenergic receptors that mediate vascular smooth muscle vasoconstriction, with an additional minor degree of beta-2 adrenergic vasodilatory activity. Phentolamine is the treatment of choice for norepinephrine extravasation as it both increases the median effective dose for vasospasm in the presence of sympathetic amines[68] and produces a greater increase in capillary blood flow in the setting of adrenoreceptor-mediated vasoconstriction.[69]

Dopamine

At high concentrations, dopamine acts as a potent alpha-1 agonist as well as promotes the release of norepinephrine from presynaptic nerve terminals. Although the treatment literature is sparser, it suggests that the management of dopamine extravasations remains largely similar to that of norepinephrine. Intradermal phentolamine may be used with a similar dosage and administration.[70] Select literature has also suggested the effectiveness of topical nitroglycerine,[71] nitroprusside,[71] and terbutaline[72] in the treatment of dopamine extravasation.

Dobutamine

Dobutamine is a beta-1 agonist known for its inotropic and chronotropic properties. Although rare, it has been known to cause dermal necrosis when extravasated due to its partial alpha-agonist activity.[73] Reasonable treatment options include terbutaline,[72] phentolamine, and nitroglycerine.[49]

Epinephrine

Epinephrine possesses nonselective activity on alpha-1, beta-1, and beta-2 adrenoreceptors. The majority of reported epinephrine extravasation events are due to inadvertent injections by autoinjector devices contained in anaphylaxis treatment kits.[49] Phentolamine may also be used in the treatment of intravenous extravasation of epinephrine in the setting of shock or cardiac arrest.[49]

Phenylephrine

When compared with other vasopressors, phenylephrine is the most selective alpha-1 agonist. Cases of phenylephrine extravasation are exceedingly rare. One French case report describes an instance of necrosis ensuing after the administration of a phenylephrine infusion for septic shock that included unsuccessful treatment with lidocaine and hyaluronidase.[74] Proper treatment of phenylephrine extravasation remains largely unknown, although phentolamine may be effective due to its alpha-1 adrenergic antagonistic properties.

Vasopressin

Vasopressin induces vasoconstriction via V1 receptor coupling. No published reports have described the successful management of vasopressin extravasation.[49] For this reason, it is recommended that vasopressin only be administered through a central line.[40]

Factors affecting degree of extravasation

Published data on tissue injury or extravasation from vasopressor administration via peripheral IVs are derived primarily from case reports and case series, making it difficult to draw definitive conclusions regarding the safety of PIV vasopressor administration.[10] However, several properties of vasopressors have been known to directly contribute to the degree of extravasation experienced, most notably the site of PIV placement and duration of vasopressor infusion.[75]

Key risk factors for adverse events associated with peripheral vasopressor administration include the use of a distal peripheral site or prolonged duration of administration.[30] The majority of local tissue injury and vasopressor extravasation events from peripheral intravenous lines involved medication delivery at a site distal to the antecubital or popliteal fossa.[10]

In cases of vasopressor extravasation from a PIV, infusion had been ongoing for an average of 35 hours.[30] These cases progressed to local tissue injury only after the infusion had been ongoing for an average of 56 hours.[10,30] The majority of extravasation events from a peripheral site resulted in no long-term sequelae or only minor disability.[30] Overall, vasopressor extravasation from a PIV is a rare occurrence.[8,46]

Differences in mortality rates of peripheral versus central catheterization

The initiation of vasopressors via a PIV catheter has not been associated with an increased risk of mortality when compared to a CVC.[76] Current guidelines recommend the administration of vasopressors within 1 hour of identification of the onset of sepsis if the patient is hypotensive during or after fluid administration.[77] This suggests that the use of a PIV catheter could prove advantageous given its ability to be placed more quickly. Observational studies suggest an association between delayed commencement of vasopressors and increased mortality in patients with sepsis,[78,79] although this finding is not consistent.[80] Delayed vasopressor administration has been associated with increased patient harm, along with prolonged hypotension and excessive fluid therapy.[81]

The lack of increased mortality risk and some improvements in the processes of care suggest that the strategy of initiating vasopressors via a PIV catheter in septic shock patients could indeed be safe.[76] Sound randomized clinical trials may still be needed to ascertain the relative risks and benefits.

Hospital policies to determine peripheral versus central catheterization

The majority of hospital policies regarding vasopressor administration prefer central administration. A recent study surveyed US-based hospitals regarding their vasopressor policies. Of this group, 15% had no policies regarding vasopressor administration. Of those that had vasopressor policies, 25% allowed only central administration, 36.5% preferred central administration, and 36.5% allowed peripheral vasopressor administration for situations outside of cardiopulmonary resuscitation.[48] Additionally, there are wide variations in other aspects of peripheral vasopressor policies, including duration limits, dose limits, and agent-type limits. Most notably, 45% of surveyed hospitals that have agent-type limits prohibit the use of peripheral norepinephrine.[48]

Variations also exist regarding minimum IV size requirements, IV site limits, and the use of ultrasound during PIV placement. In general, larger urban hospitals tended to have more PIV-friendly policies. The variability of hospital policies likely reflects the accruing but incomplete data on the optimal safety and monitoring criteria for peripheral vasopressor administration.[48]

Conclusion

There is an emerging body of evidence to suggest that the peripheral administration of vasopressors is safe and effective in many clinical contexts, and often superior to central administration. Protocolized peripheral vasopressor administration is quicker than traditional central administration, reducing the time of hemodynamic instability in the setting of shock or similar emergencies. It reduces the infectious risks of CVC placement and may eliminate the need for CVC placement entirely.[41] Data suggest that the risk of adverse events from PIV and CVC vasopressor administration are comparable.[46] Overall, peripheral extravasation events occur infrequently and complications requiring more than conservative management are extremely rare.[8]

Nonetheless, many current healthcare providers may have more experience and thus feel more comfortable with CVC vasopressor administration. In patients with equal central or peripheral venous access requirements, central venous catheters should preferably be inserted.[82]

In conclusion, peripherally administered vasopressors are emerging as a viable treatment option for increasing systemic arterial blood pressure and tissue perfusion. The short-term use of peripherally administered vasopressors in emergent situations via proximal, well-placed peripheral IV catheters is unlikely to cause local tissue injury and may effectively serve as a temporizing measure (or “bridge”) until central venous access can be obtained.[10,83] Given the findings described in this review, hospitals should consider revising their current protocols to be more accepting of temporary peripheral vasopressor administration in emergent settings, with emphasis placed on effective management plans. This will likely lead to improved patient outcomes in the treatment of shock.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.