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Clinical Investigations

Peripheral Vasoactive Administration in Critically Ill Children With Shock: A Single-Center Retrospective Cohort Study*

Levy, Robert A. MD1; Reiter, Pamela D. PharmD, BCCCP2; Spear, Matthew MD, MPH3; Santana, Alison MD4; Silveira, Lori PhD5; Cox, Shaina CPNP6; Mourani, Peter M. MD7; Maddux, Aline B. MD, MSCS8

Author Information
Pediatric Critical Care Medicine: August 2022 - Volume 23 - Issue 8 - p 618-625
doi: 10.1097/PCC.0000000000002970

Abstract

Pediatric shock is a common cause for PICU admission and mortality in the United States (1,2). The core components of resuscitation and stabilization of children in shock involves restoration of adequate tissue perfusion to ensure sufficient oxygen delivery. This is generally achieved by administration of fluids and vasoactive medications (3,4). Vasoactive medications are typically administered through a central venous catheter to optimize drug delivery and decrease the risk of medication infiltration with subsequent tissue necrosis (5,6). However, rapid acquisition of central access is not always feasible, and providers may use peripheral venous access (PVA) until central venous access (CVA) is safely obtained (6–9). Additionally, a provider may choose to exclusively use the peripheral route when duration of vasoactive support is expected to be brief. Existing adult data and some small pediatric studies suggest it may be safe and appropriate to administer vasoactive therapy peripherally in select patients (6–10). The Adult Surviving Sepsis Guidelines specifically recommend use of peripheral administration of vasoactive medications to avoid delaying restoration of mean arterial pressure while awaiting CVA (11). The pediatric guidelines do not make a recommendation regarding peripheral vasoactive administration due to a lack of evidence in children (3). There is a critical need to delineate the population and administration methods for safe use of peripheral vasoactive therapy in children (12).

We sought to describe our use of peripherally administered vasoactive therapy to critically ill children in the PICU. The objectives of this study were to: 1) characterize patients initiated on vasoactives (epinephrine, norepinephrine, or dopamine) through a peripheral venous catheter, 2) delineate characteristics of patients initiated on vasoactive support through a peripheral venous catheter who later required central venous catheter placement for ongoing vasoactive administration, and 3) describe extravasation injury associated with peripheral vasoactive infusion.

MATERIALS AND METHODS

This study received a waiver of consent from Colorado’s Multiple Institutional Review Board (protocol 16-1177).

We performed a single-center, retrospective study at an urban, quaternary-care, referral children’s hospital within a 32-bed medical/surgical PICU. Children requiring cardiac intensive care were admitted to a separate unit and were not included. We included children (31 d to 18 yr old) admitted between January 1, 2010, and December 31, 2015, who received dopamine, epinephrine, or norepinephrine. We excluded patients with thermal burns or purpura fulminans. We identified eligible patients retrospectively using data available in the electronic medical record (EMR). Patients who received at least one of the three vasoactive medications initially through a peripheral venous catheter were categorized in the PVA group, whereas those receiving the medications only through a central venous catheter were categorized in the CVA group. We extracted data from the EMR to delineate patient and clinical course characteristics such as age, sex, weight, and severity of illness based on the Pediatric Risk of Mortality (PRISM III) score (13). Primary diagnosis was extracted by chart review. We also collected data related to vasoactive administration (e.g., medication, concentration, maximum dose, and duration of administration) and catheter characteristics (e.g., size and location). Because some children received multiple concurrent vasoactive agents, some data elements were summarized by number of infusions. We evaluated the complication of tissue extravasation, interventions used to treat extravasations, and change in blood pressure due to reduced drug delivery during an extravasation event. Per unit protocol, peripheral catheter sites are checked hourly during infusion of a continuous medication. To identify extravasations and treatments of extravasations, each PVA patient’s record was reviewed including nursing documentation related to placement and removal of the peripheral catheter, nursing notes and flow sheets on days of peripheral vasoactive administration, and a search for medications commonly used to treat extravasations (hyaluronidase, nitroglycerin 2% topical, phentolamine, and terbutaline). When extravasations were identified, an additional search of the patient’s clinical notes was completed to evaluate for evidence of ongoing disability or functional impairment. Finally, clinical outcomes including cardiopulmonary resuscitation, duration of PICU stay, and mortality were also collected. Durations of mechanical ventilation and PICU length of stay were calculated based on exact date and time of initiation and discontinuation of support and admission and transfer, respectively, as documented in the EMR. Study data were stored using Research Electronic Data Capture (REDCap) tools hosted at the University of Colorado (14,15).

We performed a descriptive analysis to compare patient and clinical characteristics of patients in the PVA versus CVA groups and PVA patients who had a central venous catheter placed for ongoing vasoactive infusion versus those who did not. Patients in the PVA group who had fully weaned off vasoactive support prior to central line placement were included in the PVA group as they did not require a central catheter for ongoing vasoactive infusion. Summary statistics are provided as medians (interquartile range [IQR]) for continuous variables and counts (percentages) for categorical variables. Groups were compared using Wilcoxon rank-sum tests for continuous variables and Fisher exact test or Pearson chi-square tests for categorical data. Bonferroni correction was used to correct for multiple comparisons. Statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC).

RESULTS

We evaluated 756 children who received vasoactive therapy. The median age of the cohort was 9.4 years (IQR, 2.6–14.1), 345 (45.6%) were female, and median weight was 27.0 kg (IQR, 13.0–50.0 kg) (Table 1). The most common admitting diagnoses were septic shock (n = 197, 26.1%), respiratory infection (n = 88, 11.6%), and trauma (n = 84, 11.1%). The median PRISM III score was 9 (IQR, 5–15). The majority of patients (n = 551, 72.9%) required mechanical ventilation.

TABLE 1. - Demographic and Clinical Course Characteristics
Characteristics Entire Cohort Initial Site of Vasoactive Infusion p a
Peripheral Central
n (%) 756 231 (30.6) 525 (69.4) Not applicable
Age (yr), median (IQR) 9.4 (2.6–14.1) 10.3 (4.8–14.6) 8.5 (2.1–13.9) 0.003 b
Female, n (%) 345 (45.6) 110 (47.6) 235 (44.8) 0.48
Weight (kg), median (IQR) 27.0 (13.0–50.0) 30.9 (17.3–52.2) 25.3 (12.0–49.0) 0.001 b
Primary diagnosis, n (%)
 Sepsis/shock 197 (26.1) 93 (40.3) 104 (19.8) < 0.001 b
 Respiratory infections 88 (11.6) 30 (13.0) 58 (11.0)
 Trauma 84 (11.1) 15 (6.5) 69 (13.1)
 Seizures 44 (5.8) 15 (6.5) 29 (5.5)
 Other 343 (45.4) 78 (33.8) 265 (50.1)
PRISM III score, median (IQR) 9 (5–15) 7 (3–13) 10 (5–16) < 0.001 b
PRISM III score, median (IQR)PRISM III risk of mortality (%), median (IQR) 10.6 (6.6–20.6) 8.4 (5.1–16.7) 11.9 (6.6–22.9) < 0.001 b
7 pm to 7 am vasoactive initiation, n (%) 414 (54.7) 149 (64.5) 265 (50.5) < 0.001 b
Invasive mechanical ventilation during PICU stay, n (%) 551 (72.9) 117 (50.7) 434 (82.7) < 0.001 b
Duration of mechanical ventilation (d), median (IQR) 4.2 (1.7–9.3) 2.8 (1.1–6.0) 4.7 (1.8–10.5) < 0.001 b
Received cardiopulmonary resuscitation, n (%) 49 (6.5) 7 (3.0) 42 (8.0) 0.01
Received extracorporeal support, n (%) 29 (4.1) 4 (2.1) 25 (4.8) 0.13
PICU length of stay (d), median (IQR) 4.5 (2.0–10.9) 2.8 (1.6–6.0) 5.8 (2.4–13.3) < 0.001 b
Mortality, n (%) 144 (19.0) 24 (10.4) 120 (22.9) < 0.001 b
Standardized mortality ratio (95% CI) c 0.99 (0.85–1.18) 0.68 (0.46–1.01) 1.10 (0.92–1.32) Nonsignificant
IQR = interquartile range, PRISM = Pediatric Risk of Mortality.
ap value compares groups based on peripheral vs central site of initial vasoactive administration.
bSignificant at the p < 0.0042 level due to Bonferroni correction.
cPRISM III standardized mortality ratio.

Vasoactive therapy was initiated peripherally in 231 (30.6%) patients and centrally in 525 (69.4%) patients. Of the 231 PVA patients, 189 (82%) received dopamine, 43 (19%) received norepinephrine, and 30 (13%) received epinephrine. Fifty-three patients (23%) received more than one simultaneous vasoactive infusion via the peripheral route. Specifically, 48 PVA patients (21%) received two concomitant vasoactive infusions peripherally, and five (2%) received three. Of the 262 infusions in the PVA group, 256 (98%) had an infusion site documented. Infusions were primarily in the arm not including the hand (58%), hand (25%), and lower extremity (8%). Peripheral venous catheter size was documented in 249 infusions (95%). Catheter size was most frequently 20 or 22 gauge (75%), followed by 16 or 18 gauge (19%), and 24 gauge (6%). Dopamine concentration was most frequently 3.2 mg/ml (188/189; 99%), norepinephrine concentration was most frequently 100 mcg/mL (28/44; 64%), and epinephrine concentration was most frequently 100 mcg/mL (23/29; 79%). The highest doses administered were 10 mcg/kg/min (IQR, 7–12 mcg/kg/min), 0.05 mcg/kg/min (0.05–0.10 mcg/kg/min), and 0.10 mcg/kg/min (IQR, 0.05–0.15 mcg/kg/min) for dopamine, norepinephrine, and epinephrine, respectively. The median duration of administration was longest for norepinephrine (205 min [IQR, 120–480 min]) followed by dopamine (180 min [IQR, 120–465 min]) and epinephrine (160 min [IQR, 65–259 min]).

Patients in the PVA cohort were older compared with CVA patients (median, 10.3 yr [IQR, 4.8–14.6 yr] vs 8.5 [IQR, 2.1–13.9]; p = 0.003), larger (median, 30.9 kg [IQR, 17.3–52.2 kg] vs 25.3 [IQR, 12.0–49.0]; p = 0.001), and had lower illness severity (median PRISM III score, 7 [IQR, 3–13] vs 10 [IQR, 5–16]; p < 0.001) (Table 1). Children in the PVA cohort more frequently had vasoactive therapy initiated at night compared with the CVA cohort (64.5% vs 50.5%; p < 0.001). Patients in the PVA group were less frequently supported with mechanical ventilation compared with CVA patients (50.7% vs 82.7%; p < 0.001). Patients in the PVA group had shorter PICU stays (median, 2.8 d [IQR, 1.6–6.0 d] vs 5.8 [IQR, 2.4–13.3]); p < 0.001) and lower mortality (10.4% vs 22.9%; p < 0.001).

Of the 231 PVA patients, 124 (53.7%) ultimately had a central venous catheter placed after a median duration 140 minutes [IQR, 65–247] of peripheral vasoactive infusion (Table 2). Patients with vasoactives initiated peripherally who remained free of a central venous catheter had lower illness severity (median PRISM III score, 6 [IQR, 3–9] vs 10 [IQR, 5–16]; p < 0.001) compared with PVA patients who ultimately had a central venous catheter placed. Children in the PVA cohort who did not have a central venous catheter placed were less likely to be on mechanical ventilation during PICU admission compared with patients who had a central venous catheter placed (35.5% vs 63.7%; p < 0.001). Notably, 44 of 93 patients (47.3%) with septic shock did not undergo central venous catheter placement, and nine of 30 (30.0%) admitted for respiratory tract infection remained free of a central venous catheter. Additionally, patients who remained free of a central venous catheter had shorter PICU stays (median, 1.9 d [IQR, 1.1–3.1 d] vs 3.8 [IQR, 2.0–7.3]; p < 0.001).

TABLE 2. - Characteristics of Patients Initially Administered Vasoactives Peripherally Based on Subsequent Placement of a Central Venous Catheter
Characteristic Subsequent Placement of a Central Venous Catheter p a
No Yes
n (%) 107 (46.3) 124 (53.7) Not applicable
Age (yr), median (IQR) 12.4 (6.0–14.7) 9.3 (4.4–14.3) 0.07
Female, n (%) 53 (50) 57 (46) 0.10
Weight (kg), median (IQR) 37.2 (18.5–57.5) 26.8 (15.8–49.9) 0.04
Primary diagnosis, n (%)
 Sepsis/shock 44 (41.1) 49 (39.5) 0.07
 Respiratory tract infection 9 (8.4) 21 (16.9)
 Trauma 6 (5.6) 9 (7.3)
 Seizures 9 (8.4) 6 (4.8)
 Other 39 (36.4) 39 (31.5)
PRISM III score, median (IQR) 6 (3–9) 10 (5–16) < 0.001 b
PRISM III risk of mortality (%), median (IQR) 8.4 (5.1–16.7) 11.9 (6.6–22.9) < 0.001 b
Invasive mechanical ventilation, n (%) 38 (35.5) 79 (63.7) < 0.001 b
Duration of invasive mechanical ventilation (d), median (IQR) 2.2 (0.8–5.8) 3.1 (1.5–6.7) 0.08
Cardiopulmonary resuscitation, n (%) 1 (0.9) 6 (4.8) 0.13
Extracorporeal membrane oxygenation, n (%) 0 (0) 4 (3.9) 0.12
PICU length of stay (d), median (IQR) 1.9 (1.1–3.1) 3.8 (2.0–7.3) < 0.001 b
Mortality, n (%) c 5 (4.8) 19 (15.3) 0.009
Standardized mortality ratio (95% CI) d 0.47 (0.20–1.13) 0.77 (0.49–1.21) Nonsignificant
IQR = interquartile range, PRISM = Pediatric Risk of Mortality.
aCompares patient groups based on subsequent central venous catheter placement.
bSignificant at the p < 0.0045 level due to Bonferroni correction.
cOf the five patients who died without placement of a central line for vasoactive support, three died within 3 d of admission due to withdrawal of support in the setting of severe neurologic injury. The two remaining patients had prolonged hospitalizations, which included subsequent placement of a central venous catheter after attaining hemodynamic stability with initial vasoactive support that was administered peripherally.
dPRISM III standardized mortality ratio.

In the 231 patients in whom vasoactive therapy was initiated peripherally, four (1.7% [95% CI, 0.03–3.4]) experienced an extravasation event. Extravasations occurred exclusively in the hand: twice with infusion of peripheral epinephrine and twice with infusion of peripheral dopamine (eTable 1, https://links.lww.com/PCC/C62). The doses of vasoactive therapy at the time of the extravasations were similar to the maximum doses infused in the overall PVA group. Three extravasation events prompted administration of an antidote. Phentolamine was prescribed as an antidote for both peripheral dopamine extravasations. Terbutaline and topical nitroglycerine were prescribed as antidotes for one of the two epinephrine extravasation events. None of the extravasation events were associated with abrupt hypotension due to reduced intravascular delivery of medication or with long-term disability in the affected limb. One patient later died after withdrawal of life-sustaining support.

DISCUSSION

In this single-center, retrospective study, we compared characteristics and outcomes of critically ill children who received vasoactive therapy via a peripheral or central venous catheter. Our findings suggest that the initiation of vasoactive medications peripherally versus centrally is more frequent in older children and those who are less severely ill at the time of presentation. Importantly, patients receiving vasoactive support through a peripheral catheter experienced a low extravasation rate of less than 2%, none of which resulted in long-term disability. The current Pediatric Surviving Sepsis Guidelines published in 2020 did not issue a recommendation for or against the use of peripheral vasoactive medications in children due to a lack of evidence (3). Our study offers additional data to inform future recommendations regarding the population for whom peripheral vasoactive infusion may be appropriate and evidence that avoidance of distal extremities for peripheral vasoactive infusion may be safest, when possible.

The choice to use a peripheral catheter for initial vasoactive infusion allows for additional time to assess the patient and their clinical trajectory to better inform a decision to place a central catheter. In our study, 46% of patients initially supported with peripheral vasoactive infusion did not require central venous catheter placement for ongoing vasoactive infusion including nearly half of patients admitted to the PICU with septic shock. This finding is similar to an earlier prospective study evaluating 49 children with septic shock initiated on peripheral vasoactives in the emergency department, in which 39% of the patients admitted to the PICU did not subsequently have a central venous catheter placed (16). Patregnani et al (9) also reported that 38 of 102 PICU patients with shock were supported with only peripheral vasoactive administration. In the current study, patients who avoided central venous catheter placement for ongoing vasoactive support were larger, had lower illness severity, and required less invasive support compared with patients who ultimately had a central venous catheter placed. This may suggest that the decision to refrain from central venous catheter placement was informed, in part, by a rapidly improving clinical trajectory. Importantly, the decision to defer central line placement can avoid well-known complications associated with these catheters including local infection, central-line associated blood stream infections, dislodgment, occlusion, thrombosis, and catheter fracture (12). Our data suggest that these complications may be avoidable in some critically ill pediatric patients with shock, especially larger patients with lower illness severity.

Our study also demonstrates that the use of vasoactives through a peripheral venous catheter is associated with a low prevalence of extravasation, with an upper limit of the 95% CI for four of 231 being 1-in-30 cases. These findings are no different from the data reported by Patregnani et al (9), describing an extravasation rate of two of 102 children who received vasoactives infused peripherally. Importantly, none of the extravasation events were associated with long-term disability. Similar findings were documented in pediatric patients presenting to the emergency department in septic shock who were given peripherally administered vasoactives and in a cohort of children receiving peripheral vasoactive therapy during critical care transport (16,17).

In our cohort, all extravasation events were associated with peripheral venous catheters inserted in the hand. Similar to our findings, a large systematic review of extravasation events associated with peripheral vasoactive administration in adults also identified sites in the distal extremities as more commonly associated with extravasation events (6,10). The increased risk of extravasation associated with insertion sites in the hand has also been described across hospitalized children (18). Two of the extravasation events identified in our study were associated with peripheral vasoactive infusions that exceeded 12 hours in duration. This may be expected given that prolonged administration of a vasoconstrictive agent in a patient population with small veins may increase the risk of local tissue injury. However, the risk of extravasation with prolonged administration may not be unique to vasoactive therapy as other medications such as fluids with high electrolyte content, steroids, and antibiotics have been associated with increased risk of infiltration and extravasation in hospitalized children, particularly with prolonged administration durations (19,20).

There are several limitations to our study. As a single-center study, the generalizability of our findings is limited. Due to the retrospective nature of the study, we are only able to evaluate associations between route of vasoactive therapy and outcomes. We also recognize the limitations in comparing the PVA and CVA cohorts without more complete data delineating additional aspects of their clinical course such as time to vasoactive initiation, appropriate antibiotics in the sepsis cohort, fluid resuscitation, and lactate clearance. In addition, we were unable to differentiate between mechanical ventilation as a marker of illness severity versus a support mechanism that facilitated placement of the central venous catheter. For example, the added risk of central venous catheter placement in a nonintubated patient is likely greater than that in a patient who is already intubated as the nonintubated patient often requires sedation and, potentially, intubation to facilitate placement. Similarly, the finding of more frequent night-time initiation of vasoactive therapy in the PVA cohort may be due to differences in available resources overnight compared with daytime. Finally, due to the reliance on chart review, we were unable to identify the clinical indications directing the decision to place or avoid placement of a central venous catheter, and the retrospective data collection may have resulted in an underrepresentation of extravasations due to incomplete documentation.

Currently, our center’s approach to patients with fluid-refractory shock favors initiation of vasoactive therapy peripherally through the most proximal catheter available when a central line is not in place for another indication. Peripheral vasoactive administration is considered sufficient unless the patient has escalating or sustained, high doses of vasoactive support. In these patients or patients who require CVA for another reason, vasoactives are transitioned centrally. Prolonged periods of low-dose vasoactive support administered peripherally are often tolerated in patients who otherwise do not require central line placement, particularly if the patient is not intubated.

CONCLUSIONS

Short-term administration of vasoactive therapy via a peripheral venous catheter is associated with a low prevalence of extravasation. Peripheral vasoactive administration can offer providers an option for drug delivery while evaluating the need for a central venous catheter or to ensure safe central line placement. Given the growing evidence of safety surrounding targeted use of peripheral vasoactive infusions, it is reasonable to consider this method of vasoactive infusion in a select population of pediatric patients. Future prospective studies are needed to define the appropriate patient population and clinical indications for peripheral vasoactive drug administration.

AT THE BEDSIDE

  1. Evidence describing the use of peripheral vasoactive infusions in children with shock is limited.
  2. This single-center investigation identified that older children with lower illness severity and nighttime vasoactive initiation were more often initially supported by peripheral vasoactive infusion, and nearly half did not go on to have central venous catheter placement for ongoing vasoactive infusion.
  3. Extravasations do occur in patients receiving peripheral vasoactive infusions, and the prevalence could be as high as 1-in-30. These risks and balances of immediately starting PVA versus the consequence of delaying vasoactive infusion while waiting until central access is available must be considered by clinicians.

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Keywords:

intensive care units; pediatric; pediatrics; peripheral venous catheterization; vascular access device; vasopressor agents

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