Composition Vendor Newgen KnowledgeWorks (P) Ltd. PLoS One plos plosone PLOS One 1932-6203 Public Library of Science San Francisco, CA USA 10.1371/journal.pone.0333275 PONE-D-25-06871 Research Article Medicine and health sciencesClinical medicineSigns and symptomsSepsis Biology and life sciencesPopulation biologyPopulation metricsDeath rates Physical sciencesChemistryChemical compoundsOrganic compoundsAminesCatecholaminesNorepinephrine Physical sciencesChemistryOrganic chemistryOrganic compoundsAminesCatecholaminesNorepinephrine Biology and life sciencesBiochemistryNeurochemistryNeurotransmittersBiogenic aminesCatecholaminesNorepinephrine Biology and life sciencesNeuroscienceNeurochemistryNeurotransmittersBiogenic aminesCatecholaminesNorepinephrine Biology and life sciencesBiochemistryHormonesCatecholaminesNorepinephrine Biology and life sciencesBioengineeringBiotechnologyMedical devices and equipmentCatheters Engineering and technologyBioengineeringBiotechnologyMedical devices and equipmentCatheters Medicine and health sciencesMedical devices and equipmentCatheters Medicine and health sciencesVascular medicineBlood pressure Biology and life sciencesAnatomyBody fluidsUrine Medicine and health sciencesAnatomyBody fluidsUrine Biology and life sciencesPhysiologyBody fluidsUrine Medicine and health sciencesEpidemiologyMedical risk factors Physical sciencesChemistryPolymer chemistryMacromoleculesPolymersPolyvinyl chloride Physical sciencesMaterials scienceMaterialsPolymersPolyvinyl chloride Physical sciencesChemistryPolymer chemistryPolymersPolyvinyl chloride Peripheral line for vasopressor administration: Prospective multicenter observational cohort study for survival and safety Peripheral line for vasopressor administration: Prospective cohort study for survival and safety Petros Adane Conceptualization Data curation Formal analysis Funding acquisition Resources Supervision Visualization Writing – original draft 1 Melkie Addisu Conceptualization Data curation Formal analysis Funding acquisition Supervision Validation Visualization Writing – original draft Writing – review & editing 1 https://orcid.org/0000-0002-4195-0243 Kotiso Kehabtimer Shiferaw Conceptualization Data curation Formal analysis Supervision Validation Visualization Writing – original draft Writing – review & editing 2 Kebede Dawit Conceptualization Data curation Formal analysis Resources Validation Visualization Writing – original draft Writing – review & editing 1 Oljira Chala Fekadu Conceptualization Data curation Formal analysis Validation Visualization Writing – original draft Writing – review & editing 1 https://orcid.org/0000-0001-9219-513X Assefa Gemechu Fitsum Formal analysis Supervision Writing – original draft Writing – review & editing 3 * Yusuf Hanan Formal analysis Supervision Writing – original draft Writing – review & editing 1 Abebe Sintayehu Writing – original draft Writing – review & editing 1 Ashagre Aschalew Writing – original draft Writing – review & editing 1 Bekele Amsalu Writing – original draft Writing – review & editing 1 https://orcid.org/0000-0003-1549-3939 Yohannes Andargew Writing – original draft Writing – review & editing 1 https://orcid.org/0000-0001-5880-3365 Etesa Eyob Kebede Writing – original draft Writing – review & editing 4 Bedru Mohammed Writing – original draft Writing – review & editing 5 Gebremariam Tewodros Haile Conceptualization Data curation Formal analysis Supervision Writing – original draft Writing – review & editing 1 Department of Internal Medicine, Addis Ababa University, College of Health Sciences, Addis Ababa, Ethiopia Department of Public Health, Werabe University, College of Health Sciences, Werabe, Ethiopia Addis Ababa University, College of Health Sciences, School of Medicine, Addis Ababa, Ethiopia East African Training Initiative, Addis Ababa, Ethiopia Cardiac Center Ethiopia, Addis Ababa, Ethiopia Sharma Kamal Editor UN Mehta Institute of Cardiology and Research Center, INDIA

No authors have competing interests.

 * E-mail: fitseaakfd@gmail.com 13102025 2025 20 10 e0333275 2622025 1192025 2025 Petros et al This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background

The placement of a central venous catheter (CVC) is associated with a high risk of central line-related bacteremia and mechanical complications. In a resource-constrained environment, the use of CVC is limited as a result of the complexity of the procedure and the need for a trained expert to place it. There is scant evidence on the feasibility, outcome, and safety of administering vasopressors using a peripheral venous catheter (PVC). Hence, our study, which is the first of its kind, evaluated the survival outcome, predictors, and safety of vasoactive drug administration via peripheral intravenous access in patients with circulatory shock.

 Methods

A prospective cohort study was conducted in the Emergency Department and ICU setting of selected public and private hospitals in Addis Ababa on selected 250 circulatory shock patients over 6 months for whom vasopressor was administered peripherally. Data was collected daily using ODK by study site coordinators and trained data collectors. Statistical analysis was done using STATA 14.1 using descriptive analysis, Kaplan Meir survival analysis, and cox regression analysis.

 Results

The median (IQR) age of the participants was 48.5 (35, 62). From circulatory shock causes, septic and cardiogenic shock accounted for 69.6% and 22.0% respectively. There were 3 extravasation injuries from the 250 patients that occurred exclusively on patients that took vasopressor for more than 4 days yielding an event rate of 1.2% and 0.004/patient day. Mortality in circulatory shock patients is high with a 57.6% mortality rate in general and 67.8% in septic shock patients. A Cox regression analysis identified decreased baseline systolic blood pressure [AHR = 0.98; 95%CI: 0.95, 0.99], decreased urine output [AHR = 0.96; 95%CI: 0.93, 0.99], septic shock compared to cardiogenic shock [AHR = 0.48; 95%CI: 0.24, 0.94], and use vasopressor other than norepinephrine [AHR = 0.6; 95%CI: 0.39, 0.92] as independent predictors of death of circulatory shock patients with peripherally administered vasopressors.

 Conclusion

Our study found that peripheral venous catheter use for vasopressor administration in circulatory shock was associated with a low extravasation rate (1.2%), with all events occurring after more than five days, indicating it might be a safe alternative to CVC for short-term use in resource-limited settings. Findings support cautious prolonged use and consideration of central access when therapy exceeds a few days. This calls for randomized controlled trials to compare the safety and efficacy of vasopressor administration by PVC versus CVC.

 Addis Ababa University College of Health Sciences N/A The funding for this research was acquired from Addis Ababa University, College of Health Sciences Research grant. Data Availability All relevant data are available in a public repository at the following link: https://doi.org/10.5281/zenodo.16872086. Introduction

Shock is a common condition in critical care, affecting about one-third of patients in the intensive care unit (ICU) that requires urgent intervention to decrease the high mortality associated with it [1]. It is defined as an acute or hyperacute physiological derangement, a systemic syndrome characterized by signs and symptoms of different organ hypo perfusion [2]. Circulatory shock is commonly caused by septic shock, a form of distributive shock which is the most common form of shock among patients in the ICU, followed by cardiogenic, hypovolemic shock, and obstructive shock [3]. Vasoactive medications (VMs) are often required to improve hemodynamic function in patients with shock [4]. They are usually given through central venous catheter (CVC). This is primarily out of concern that extravasation of peripheral intravenous (PIV) access may result in local tissue injury due to the vasoconstrictive effect of the VM. Evidence for this hypothesis was based on a systematic review for which case reports and case series contribute a significant share [5]. However, insertion of CVC is associated with a variety of mechanical complications and a risk of central line-associated bacteremia of around 15% [6]. Both central line-associated bacteremia and mechanical complications of CVC increase the length of hospital stay, mortality, and health care cost. The previous recommendation of early goal-directed therapy by Rivers et al described the use of a series of “goals” that included measurement of central venous pressure (CVP) and central venous oxygen saturation (Scvo2) which requires central venous catheter insertion for monitoring septic shock [7]. This approach has now been challenged as three large multicentric randomized control trials failed to show a mortality reduction [8–10]. Based on the three RCTs currently, major guidelines do not recommend central venous catheter insertion for septic shock intervention monitoring over the usual bedside patient monitoring [4], which has limited the role of central venous catheter insertion in shock patients to the administration of vasoactive agents. The evidence on feasibility, outcome and safety of using vasoactive medications via Peripheral intravenous access for circulatory shock patients is mostly based on case reports and case series. There are limited prospective studies on the safety and outcomes of vasoactive medication administration via peripheral intravenous lines, and none have an adequate sample size or extend beyond a single institution. [11–13]. Despite the poor quality of existing evidence, vasoactive medication-related peripheral necrosis can lead to significant morbidity and negatively impact patient outcomes. A well-designed, prospective multicenter cohort study with a sufficient sample size is needed to evaluate the safety and efficacy of administering vasoactive medications through peripheral intravenous access in patients with circulatory shock, as current recommendations to use CVC for vasopressor administration are primarily based on case reports, case series, and small observational studies. Our study aims to assess the safety and outcome of administration of vasoactive medication via Peripheral venous line for circulatory shock patients.

 Methods and materials Study setting

The study was conducted in the Emergency Department and Intensive Care Units (ICUs) of public and private hospitals in Addis Ababa, Ethiopia, over a six-month period (May 1, 2021 – November 20, 2021). The participating hospitals with ICUs included Tikur Anbessa Specialized Hospital, Yekatit 12 Hospital, Eka Kotebe Hospital, Saint Peter Hospital, and Betezata Hospital.

 Study design and sampling

A Prospective cohort study design was used to assess the outcome and safety of administration of vasoactive medications via peripheral intravenous access for circulatory shock patients. The sample size was calculated using Epi info stat calc software for descriptive study with an event rate of 6% from Kamal et al study with an acceptable margin of error of 3% (reduced from the default value of 5% to increase the sample size) and 95% confidence interval(Z = 1.96). Design and clusters effect of 1 was used as this is a single center study with consecutive individual patients.

n= Z2 P(1−P)d2

N = 241

Adjusting for a non-response rate of 5%, the total sample size was 254. All subsequent patients in the study area who fulfilled the inclusion criteria were included.

In this study, the observed extravasation rate was 1.2%, compared to the expected rate of 6% from prior literature. A post hoc power analysis, based on the observed absolute reduction and a two-sided alpha level of 0.05 was done. The result was 89% power to detect this effect. This highlighted that the study had sufficient power.

 Inclusion criteria

Any adult patients, age ≥ 18-year-old for whom vasoactive medications were administered through PIV access for more than 1 hour were included in the study.

 Exclusion criteria

Non-traumatic amputation in any of the limbs

Cardiac Arrest before initiation of vasoactive agents

 Operational definition

Safety of vasoactive medication administration via peripheral line was assessed in terms of extravasation injury and survival outcome. Minor safety considerations including changing peripheral access site because of malfunctioning were also included in the safety assessment.

Circulatory shock is defined in our study as a requirement for vasoactive medication to improve patients’ blood pressure/ hemodynamics by the treating team.

Extravasation injury posing threat to the limb was considered a major safety concern.

Extravasation injury was defined as an injury in a peripheral access limb that includes irritation (pain), swelling, discoloration, and gangrene using the society of infusion nurses’ infiltration scale. Vasoactive medications associated with peripheral line extravasation injury in this study include norepinephrine, epinephrine, phenylephrine, and dopamine.

Peripheral intravenous access is defined as venous access in the external jugular, upper arm, antecubital fossa, forearm hand, wrist, lower leg, and foot.

Death as a patient outcome was labeled whenever the patient dies before discontinuation of the vasoactive agent or in a 07- day follow-up period.

 Ethics approval and consent to participate

Informed written consent was collected from participants of the study or their next of kin if the patient was unable to give informed consent. Ethical clearance was obtained from the AAU CHS department of the Internal Medicine department review board. The safety and privacy of subjects were protected by using their de-identified information during the data collection and analysis process.

 Data collection techniques

A standardized case report format (CRF) was prepared to collect enrolled patient’s data on demographics, indication for vasoactive medication, baseline risk factors for complications, PIV access site, the gauge of the catheter, Duration of Vasoactive medication, type of vasoactive medication, dilution of vasoactive medication, Infusion rate, Timing of complication and patient's outcome.

Follow-up for a patient receiving a vasoactive agent was discontinued under any of the following four conditions:

If the patient dies

If the Vasoactive agent is discontinued by the treating physician

If the Patient develops extravasation injury

When the study period is completed (07 days)

Data on all variables were collected using ODK by trained data collectors (residents, internists, and general practitioners) using the CRF prepared by the research team supervised by study site coordinators.

 Data quality and management

To ensure the quality of the data, pre-test data were collected on 5% of the sample size population from patients’ medical records retrospectively in Tikur Anbessa Hospital, Addis Ababa University, and training was given to data collectors in Addis Ababa for one day before the survey to ensure consistency and reduce Intra and inter observation difference on the measurement of variables. The collected data were checked for completeness and consistency on each day of data collection. Daily supervision and monitoring were conducted by the assigned supervisors and principal investigators.

 Data processing and analysis

After data collection, survey responses obtained via ODK were converted to CSV and SPSS formats and then exported to Stata version 14.0 for analysis. Descriptive statistics, Kaplan-Meier survival plots, and Cox regression analysis were performed. Continuous variables were presented as mean (SD) or median (IQR), while categorical variables were reported as frequencies or percentages. Survival analysis was conducted to assess the mortality rate and complications associated with the administration of vasoactive medications via peripheral venous access in circulatory shock patients and to identify key determinants. A p-value of <0.05 was considered statistically significant in determining the impact on outcomes and complication rates.

 Result Clinical, vasopressor-related, and laboratory characteristics of the participants

In this study, 250 shock patients requiring vasopressor participated yielding a response rate of 98.4%. The median (IQR) age of the participants was found to be 48.5 [35−62] years. Nearly three-fourths (73%) of the patients were less than 60 years old. Among the participants, half of them were female 123 (49.2%). Approximately two-thirds (66.4%) of the study participants received their vasopressor in the ICU, while one-third (33.6%) received it in the emergency department. The commonest cause of circulatory shock was septic shock accounting for approximately 70% followed by cardiogenic shock which accounted for 22% of the patients. Among Comorbidities associated with a higher risk of extravasation, diabetes mellitus and hypertension were present in approximately 14.0% and 14.4% of patients, respectively. Nearly one fourth (23.6%) of the circulatory shock patients were COVID-19 positive (Table 1).

10.1371/journal.pone.0333275.t001Clinical characteristics of vasopressor requiring shock patients admitted in hospitals with ICU capacity.
Variables (n = 250) n (%)
Age in year 18–40 83 (33.2)
41–60 100 (40)
>60 67 (26.8)
Sex Male 127 (50.8)
Female 123 (49.2)
COVID-19 Status Yes 59 (23.6)
No 163 (65.2)
Unknown 28 (11.2)
Comorbidities Diabetes mellitus 35 (14)
Hypertension 36 (14.4)
Ischemic Heart Disease 23 (9.2)
Reynaud’s Phenomenon 1 (0.4)
Smoking 3 (1.2)
Vasculitis 2 (0.8)
Stroke 19 (7.6)
Liver diseases 11 (4.4)
HIV/AIDS 17 (6.8)
SLE/APS 2 (0.8)
Type of shock Septic shock 174 (69.2)
Cardiogenic shock 55 (22)
Obstructive shock 11 (4.4)
Hypovolemic shock 19 (7.6)
Septic vs Cardiogenic not settled 14 (5.6)
Was Systolic blood pressure > 90 achieved within 24 hours Yes 170 (68)
No 80 (32)

Table 2 shows vasopressor administration-related data of the study participants. Among the study participants, three-fourths (76.8%) took their vasopressor through the left extremity. Most (70%) of circulatory shock patients received their vasopressor from the peripheral venous catheter in the arm (42%) followed by the antecubital area (28%). Among the study participants, 58.8% and 23.6% took their vasopressor using 18-gauge and 20-gauge PVC. The most commonly used vasoactive agent was Norepinephrine (57.6%) followed by Epinephrine (41.6%). Around two-thirds (68.0%) of the circulatory shock patients achieved systolic blood pressure above 90-millimeter mercury (mmHg) within 24 hours of vasopressor initiation (Table 2).

10.1371/journal.pone.0333275.t002Vasopressor administration-related data of vasopressor requiring shock patients admitted in hospitals with ICU capacity.
Variables (n = 250) n (%)
Location of the venous access External jugular 12 (4.8)
Upper arm 6 (2.4)
Antecubital fossa 70 (28)
Forearm 106 (42.4)
Hand 47 (18.8)
Wrist 6 (2.4)
lower leg 1 (0.4)
Foot 2 (0.8)
Patients dominant hand Right 235 (94)
Left 15 (6)
Location of the venous access left extremity 192 (76.8)
Right Extremity 58 (23.2)
Intravenous catheter size in gauge Green (18) 147 (58.8)
Pink (20) 59 (23.6)
Blue (22) 43 (17.2)
Yellow (24) 1 (0.4)
Vasoactive agent used Norepinephrine 144 (57.6)
Dopamine 17 (6.8)
Epinephrine 104 (41.6)
Was SBP > 90 mmHg achieved within 24 hours Yes 170 (68)
No 80 (32)

The median Glasgow coma scale for study participants was 14 [IQR: 10–15] while the median systolic and diastolic blood pressure in mmHg before the initiation of vasopressor was 74.5 [IQR: 70–80] and 50 [IQR: 40–50] respectively. The median platelet count [103] of the study participants was 186 [IQR: 126–271.5] while the median absolute neutrophil count [103] was 9.6 [6.1, 15.3%]. The median urine output over 24 hours in ml was 400 [IQR: 300–1500]. Circulatory shock patients took norepinephrine during maximum infusion with a median dose of 0.25 [IQR: 0.2–0.5] mcg/kg/ ml. The patients also took the vasopressors for a median duration of 2.1 [IQR: 1.2–2.6] days (Table 3).

10.1371/journal.pone.0333275.t003Measurement values of vasopressor requiring shock patients admitted in hospitals with ICU capacity.
Variables Median (IQR)
GCS (Glasgow coma scale) 14 (10, 15)
Systolic blood pressure before the initiation of vasopressor in mmHg 74.5 (70, 80)
Diastolic blood pressure before the initiation of vasopressor in mmHg 50 (40, 50)
Total WBC count * 10^3 11.05 (8, 16.7)
ANC (neutrophil count) *10^3 9.6 (6.1, 15.3)
ALC (lymphocyte count) *10^2 8.1 (3.9,12.3)
Hemoglobin in g/dl 11.9 (9.6, 13.6)
Platelet count *10^3 186 (126, 271.5)
SGOT 47 (26.9, 79.25)
SGPT 33 (19, 59.95)
ALP 120 (77.5, 189.5)
Total Bilirubin 1.3 (0.6, 3.2738)
Direct Bilirubin 0.47 (0.2, 1.58)
Albumin 2.425 (2.1, 3.02)
Creatinine 1.09 (0.67, 2.1)
Urea 45 (24, 76.745)
PT 16.8 (14.7, 21.4)
aPTT 32 (25.3, 43.8)
INR 1.45 (1.2, 1.8)
Urine output over 24 hr in ml 400 (300, 1500)
Infusion rate of Norepinephrine during initiation in mcg/kg/min 0.05 (0.05, 0.1)
The infusion rate of Dopamine during initiation in mcg/kg/min 5 (5, 7.5)
Infusion rate of epinephrine during initiation in mcg/kg/min 0.1 (0.1, 0.1)
The total duration of vasoactive agent administration in days 2.1 (1.2, 2.6)
Infusion rate of Norepinephrine during maximum infusion in mcg/kg/min 0.25 (0.2, 0.5)
The infusion rate of Dopamine during maximum infusion in mcg/kg/min 10 (7.5, 27.5)
Infusion rate of epinephrine during maximum infusion in mcg/kg/min 0.3 (0.2, 0.5)
Safety, survival outcome, and determinants

The mortality rate in circulatory shock patients was 57.6% with a 95% CI (51.3, 63.6). Septic shock patients have the highest mortality with 07 days mortality rate of 67.8% compared to 37.7% among cardiogenic shock patients.

Extravasation injury was rare among circulatory shock patients for whom vasopressor was administered with PVC with an incidence rate of 3 in 250 patients that took vasopressor for 750 days (1.2%) and 0.004 per/patient day. None of the extravasation injuries occurred in patients that took vasopressor for less than 05 days despite taking a maximum concentration of Norepinephrine of as high as 1 mcg/kg/min and a mean infusion rate of 0.3mcg/kg/min. The three patients with extravasation injury in our study are patients that took vasopressor via peripheral line in the hand for 05 days or more. All three patients subsequently died due to unresponsive circulatory shock with multi-organ failure. Two patients developed localized erythema and swelling of the hand, which did not require active management before their death. One patient experienced hand swelling and dark discoloration while on vasopressor therapy but died before the extent of the hand injury could be determined, despite receiving mechanical ventilator support and renal replacement therapy.

Before fitting the data to any model, the proportional hazards assumption was assessed for each covariate using the Kaplan-Meier survival plot. The results indicated that the survival curves were approximately parallel (Figs 1 and 2). However, visual inspection alone was not sufficient to confirm proportionality. Therefore, the proportional hazards assumption was further evaluated using the Schoenfeld residual test The test results were insignificant (p > 0.05) for all covariates, indicating that the assumption was met. Additionally, the global test was also insignificant, confirming that the proportional hazards assumption held (Table 4).

10.1371/journal.pone.0333275.t004Schoenfeld residual tests.
Covariates ρ χ² (1 df) P value
Baseline systolic BP 0.164 3.02 0.085
Norepinephrine (Yes/No) 0.139 2.15 0.146
Urine output (100 mL) 0.104 1.20 0.277
Shock = Cardiogenic –0.077 0.65 0.421
Shock = Hypovolemic 0.085 0.80 0.373
Pulmonary embolism –0.054 0.32 0.572
Shock = Septic 0.005 0.003 0.959
Global test: χ² = 8.14 (df = 7), p = 0.32.
10.1371/journal.pone.0333275.g001Kaplan-Meier survival curve by type of shock among vasopressor requiring shock patients. 10.1371/journal.pone.0333275.g002Kaplan-Meier survival curve by norepinephrine administration status of vasopressor requiring shock patients admitted in hospitals with ICU capacity, Addis Ababa, 2021.

We have applied the cox model to see the effects of covariates on the outcome of interest (death) of patients. Variables with p-values of less than 0.25 from the univariable analysis were screened for multivariable analysis in the Cox-proportional hazard model. Variables include age, COVID-19 positivity, Sex, Baseline Systolic blood pressure, Urine output over 24 hours in ml, the Infusion rate of Norepinephrine during maximum infusion, serum albumin, Platelet in 103, Absolute Neutrophil count in 103, Type of shock, Creatinine, and Norepinephrine administration were a candidate for multivariable analysis. From these variables, some of the variables also were significant in multivariable cox regression at a p-value of 0.05.

For a 10 mmHg increase in systolic blood pressure, the hazard of death decreased by 20 percent keeping other covariates constant [AHR = 0.98; 95% CI (0.95–0.99)].

For those patients who were presented with cardiogenic shock, the hazard of death was decreased by 52% as compared to those patients who presented with septic shock keeping other covariates constant [AHR = 0.48; 95% CI (0.24, 0.94)]. For each 100 ml increase in urine output, the hazard of death decreased by 4% keeping the other covariates constant [AHR = 0.98; 95% CI (0.93–0.99)]. Norepinephrine use as compared to the use of other vasopressors decreased the hazard of death by 40% keeping the other covariates constant [AHR = 0.60; 95% CI (0.39–0.92)] (Table 5).

10.1371/journal.pone.0333275.t005Bivariable and multivariable cox regression results of predictors of survival outcome among vasopressor requiring shock patients.
Variable Death CHR (95% CI) AHR (95% CI) P-value
Yes No
Baseline systolic blood pressure in mmHg 70 (67, 80)¥ 80 (70, 80)¥ 0.80 (0.70, 0.92) 0.98 (0.95, 0.99) 0.038*
Type of shock
 Septic 103 (67.8%) 49 (32.2%) 1 1
 Cardiogenic 20 (37.7%) 33 (62.3%) 0.35 (0.19, 0.64) 0.48 (0.24, 0.94) 0.033*
 Hypovolemic 10 (52.6%) 9 (47.4%) 0.69 (0.45, 1.34) 0.78 (0.39, 1.54) 0.472
 Card vs Septic 7 (50%) 7 (50%) 0.54 (0.45, 0.91) 0.42 (0.15, 1.18) 0.099
Pulmonary embolism 4 (40%) 6 (60%) 0.43 (0.28, 1.20) 0.54(0.18, 1.57) 0.256
Norepinephrine
 Yes 79 (54.9%) 65 (45.1%) 0.46 (0.18, 0.84) 0.60 (0.39, 0.92) 0.019*
 No 65 (61.3%) 41 (38.7%) 1 1
24-hour urine output in 100 ml 4 (2, 10)¥ 10 (4, 16)¥ 0.87 (0.54, 0.97) 0.96 (0.93, 0.99) 0.012*

*Statistically significant at a p-value of < 0.05 ¥ Median (Q1, Q3)

 Discussion

Our study is the first well-designed, prospective, multicenter study to evaluate the safety, survival outcomes, and determinants of poor prognosis associated with vasopressor administration via peripheral intravenous lines in patients with circulatory shock. Extravasation injury is rare among patients receiving vasopressor via peripheral line. Cox regression analysis identified baseline systolic blood pressure, urine output, type of shock, and norepinephrine use as independent predictors of survival in patients receiving peripherally administered vasopressors.

Current guidelines recommend CVC for vasopressor administration based on a systematic review of case reports and case series which reported limb-threatening extravasation injury with vasopressor administration via PVC [5]. However, our study aligns with findings from retrospective studies and protocolized observational studies with limited patient populations, demonstrating a low complication rate associated with peripheral vasopressor administration.[11,13]. Our patient cohort included a higher proportion of individuals at risk for extravasation injury based on established risk factors identified in previous studies. Several factors contributed to this increased risk, including a significant prevalence of Comorbidities that predispose patients to extravasation, variability in vasopressor concentrations and dosing, frequent placement of peripheral venous lines (PVLs) in high-risk locations, and the absence of a standardized protocol for managing extravasation events.

This contrasts sharply with previous studies on peripheral vasopressor administration, which were conducted on smaller patient populations and implemented strict safety protocols, including ultrasound-guided PVL insertion. Despite the substantial differences in risk factors between our study population and those in prior reports, we observed a comparable incidence of extravasation events.

Extravasation injury with peripheral line administration of vasopressors in circulatory shock patients in our study is rare with an incidence rate of 3 in 250 patients that took vasopressor for 750 days (1.2% patients or 0.004 per/patient days). This is in line with Cardenas-Garcia et al report and Delgado et al report of an extravasation event rate of 2% and 5% respectively, all of which were managed with local phentolamine injection, and led to no major complications in their retrospective and small sample size studies [12,14]. None of the extravasation injuries occurred in patients that took vasopressor for less than 5 days in our patient cohort. This suggests that vasoactive medications administration via peripheral line is safe for the duration of up to 4 days in terms of the risk of extravasation.

Unlike circulatory shock patients in other settings, our study population was relatively young, with a median age of 48 years and approximately 70% of patients under 60 years old. Despite being the youngest cohort compared to previous studies, the mortality rate remained high, particularly among patients with septic shock. The seven-day mortality rate was 52% for all circulatory shock patients and 67% for those with septic shock. This high mortality in septic shock patients in our cohort is in sharp contrast to the mortality rate of 20–50% in most septic shock cohorts from previous studies [7,15]. We concluded this difference is not related to peripheral line use in our study because cardiogenic shock patients in our study have a lower mortality rate than previous cohorts that use CVC. Besides, around 68% of our cohort patients have achieved SBP above 90 within 24 hours of vasopressor initiation which is comparable with previous studies. The mortality rate of cardiogenic shock patients in our cohort is 37.7% in sharp contrast to a reported mortality rate of around 70–75% from studies in high-income settings [16]. This is explained by the younger age of our patients and the predominant non-ischemic cause for the cardiogenic shock unlike the previous studies [17]. While the high mortality rate among septic shock patients in our study warrants further investigation to identify underlying causes, we attribute it primarily to inadequate general supportive care and delays in initiating septic shock management bundles. However, the persistently high mortality rate in septic shock patients, despite the younger age of our cohort, highlights the need for additional studies to explore contributing factors and for quality improvement initiatives to enhance patient outcomes.

Cox regression analysis identified baseline systolic blood pressure, urine output, type of shock, and norepinephrine use as independent predictors of outcomes in circulatory shock patients receiving peripherally administered vasopressors. These findings align with previous studies that have examined prognostic factors in septic and cardiogenic shock.

The hazard of death in circulatory patients in our cohort was lower with the use of norepinephrine. This is in line with previous studies that show lower mortality and arrhythmia complications with the use of norepinephrine compared with dopamine and epinephrine use [3,15]. The requirement of a higher dose of norepinephrine increased the hazard of poor outcomes in circulatory shock, finding congruent with previous cohort studies [18]. This could be explained by an underlying severe disease state which requires higher doses of norepinephrine.

Decreased urine output was associated with an increased hazard of poor outcomes. A similar finding was observed in previous studies on circulatory shock [19]. This could be explained by the fact that derangement in renal function is associated with severe circulatory shock with multiple organ failure.

A peculiar finding in our study is the lower hazard of mortality in cardiogenic shock patients in comparison to septic shock with a hazard ratio of AHR 0.48. This is in sharp contrast to the higher mortality rate of cardiogenic shock in comparison to septic shock in the western setup [3]. The lower mortality rate among cardiogenic shock patients in our cohort can be attributed to their younger age and differences in the underlying causes of cardiogenic shock. Notably, myocardial infarction-related cardiogenic shock, which is associated with poor outcomes, was less prevalent in our study population.

Limitations of the study

A key strength of this study is its multicenter, prospective cohort design, which included daily follow-up of circulatory shock patients over a seven-day period and incorporated survival analysis. This approach allowed for a detailed assessment of extravasation injury in terms of inpatient days and enabled precise documentation of the duration of vasopressor administration via peripheral venous catheters (PVCs) associated with an increased risk of extravasation.

However, several limitations should be noted. First, the absence of a control group, such as patients receiving vasopressors via central venous catheters (CVCs), limits direct comparisons and causal inference regarding the relative safety of PVC versus CVC administration. Due to severe resource limitations in the study setting, CVC insertion is rarely practiced, making a randomized controlled trial infeasible at present. Nevertheless, the current findings can serve as an important foundation for future RCTs on this topic.

Finally, the mortality rates observed in this study (57.6% overall and 67.8% among patients with septic shock) are notably higher than those reported in comparable studies. This discrepancy may be explained by several potential confounders, including late presentation of patients, limitations in ICU resources, higher baseline severity of illness, and delays between the decision to initiate vasopressor therapy and its actual administration. These factors should be considered when interpreting the study’s findings.

 Conclusion

This study suggests that peripheral venous catheter (PVC) use for vasopressor administration in circulatory shock may be a practical alternative in resource-limited settings, particularly for short-term use. While the rate of extravasation was low (1.2%), all events occurred after more than five days of vasopressor administration, highlighting an increased risk with prolonged use. These findings indicate the need for clinicians to exercise caution and consider transitioning to central venous access when vasopressor therapy is anticipated to extend beyond a few days. Current guidelines, which mandate central venous catheter insertion in emergency settings, may warrant reassessment in light of these results, though the potential risks of long-term peripheral administration must be emphasized. Nevertheless, given the study’s limitations, particularly the absence of a control group, further research is needed. Randomized controlled trials comparing the safety and efficacy of vasopressor administration via PVCs versus CVCs are essential to establish evidence-based recommendations.

 References Sakr Y, Reinhart K, Vincent J-L, Sprung CL, Moreno R, Ranieri VM, et al. Does dopamine administration in shock influence outcome? Results of the Sepsis Occurrence in Acutely Ill Patients (SOAP) Study. Crit Care Med. 2006;34(3):589–97. doi: 10.1097/01.CCM.0000201896.45809.E3 16505643 Bonanno FG. Clinical pathology of the shock syndromes. Clin Pathol Shock Syndr J Emerg Trauma Shock. 2011;4(2):233–43. doi: 10.4103/0974-2700.82211 Soong JTY, Soni N. Circulatory shock. Med. 2013;41(2):64–9. Rhodes A, Bs MB, Co-chair R, Evans LE, Co-chair F, Alhazzani W. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304–77. doi: 10.1007/s00134-017-4683-6 Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015;30(3):653.e9–17. doi: 10.1016/j.jcrc.2015.01.014 25669592 Keng L-T. Complications of central venous catheterization. N Engl J Med. 2016;374(15):1491. doi: 10.1056/NEJMc1600131 27074078 Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2001;345(19):1368–77. doi: 10.1056/NEJMoa010307 11794169 Bailey M, Bellomo R, Peter A, Cooper DJ, Higgins AM, Hold A, et al. Goal-directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371(16):1496–506. doi: 10.1056/NEJMoa1404380 Harrison DA, Sadique MZ, Grieve RD. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med. 2015;372(14):1301–11. doi: 10.1056/NEJMoa1500896 Investigators TP. A randomized trial of protocol-based care for early septic shock. N Engl J. 2014;370(18):1683–93. doi: 10.1056/NEJMoa1401602 Lewis T, Merchan C, Altshuler D, Papadopoulos J. Safety of the peripheral administration of vasopressor agents. J Intensive Care Med. 2019;34(1):26–33. doi: 10.1177/0885066616686035 28073314 Cardenas-garcia J, Schaub KF, Belchikov YG, Narasimhan M. Safety of peripheral intravenous administration of vasoactive medication. J Hosp Med. 2015;10(9):581–5. doi: 10.1002/jhm.2394 Medlej K, Kazzi AA, El Hajj Chehade A, Saad Eldine M, Chami A, Bachir R, et al. Complications from administration of vasopressors through peripheral venous catheters: an observational study. J Emerg Med. 2018;54(1):47–53. doi: 10.1016/j.jemermed.2017.09.007 29110979 Delgado T, Wolfe B, Davis G, Ansari S. Safety of peripheral administration of phenylephrine in a neurologic intensive care unit: A pilot study. J Crit Care. 2016;34:107–10. doi: 10.1016/j.jcrc.2016.04.004 27288620 Albert Schweitzer Hospital, Lambarene, Gabon, and Institute of Tropical Medicine, University of Tübingen, Tübingen G. 需要引用的霍奇金第二肿瘤New England Journal. N Engl J Med. 2011;365:687–96. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–86. doi: 10.1056/NEJM199309303291401 8366922 Vahdatpour C, Collins D, Goldberg S. Cardiogenic Shock. J Am Heart Assoc. 2019;8(8):1–12. Nandkeolyar S, Doctorian T, Fraser G, Ryu R, Fearon C, Tryon D, et al. Predictors of In-hospital mortality in cardiogenic shock patients on vasoactive or inotropic support. Clin Med Insights Cardiol. 2021;15. doi: 10.1177/11795468211049449 34720602 Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock Richard. Physiol Behav. 2017;176(1):139–48. 10.1371/journal.pone.0333275.r001 Decision Letter 0 Sharma Kamal Academic Editor 2025 Kamal Sharma This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 0

24 Mar 2025

PONE-D-25-06871Peripheral Line for Vasopressor Administration: Prospective multicenter Observational Cohort study for survival and safetyPLOS ONE

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PLOS ONE

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Additional Editor Comments :

Hello,

Thanks for assigning this paper for my review. I agree with both reviewers that though science intended is great but it lacks on 3 important aspect and needs major revision viz. Retrospective nature, lack of control arm and statistical analysis needs to be looked into. Despite 1 reviewer suggesting rejection I want to be fair to the authors to address these concerns if they can aptly act on the same.

Methodological Considerations: The study lacks a control group (e.g., patients receiving vasopressors via central venous catheters), which limits causal interpretations. This should be explicitly acknowledged as a limitation. The sample size calculation requires further justification, including a power analysis to confirm its adequacy. The high mortality rate (57.6%), particularly in septic shock (67.8%), is significantly higher than in prior studies. The analysis should better account for confounding factors such as ICU care quality and time to vasopressor initiation.

Statistical and Data Availability Issues: Confidence intervals (CIs) are not consistently reported for hazard ratios, which impacts the interpretation of findings. Effect size measures should be included to assess clinical relevance. Data are not fully available, as required by PLOS ONE. The authors should consider depositing the dataset in a public repository.

Thanks

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: N/A

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: As an intensivist myself, I do thank you for this valuable study addressing the safety of peripheral venous catheter administration of vasopressors in circulatory shock patients. Your multicenter prospective approach provides important insights, and the use of Kaplan-Meier and Cox regression analysis strengthens the statistical methodology. However, several areas require improvement to enhance the clarity, rigor, and reproducibility of the findings.

Methodological Considerations: The study lacks a control group (e.g., patients receiving vasopressors via central venous catheters), which limits causal interpretations. This should be explicitly acknowledged as a limitation. The sample size calculation requires further justification, including a power analysis to confirm its adequacy. The high mortality rate (57.6%), particularly in septic shock (67.8%), is significantly higher than in prior studies. The analysis should better account for confounding factors such as ICU care quality and time to vasopressor initiation.

Statistical and Data Availability Issues: Confidence intervals (CIs) are not consistently reported for hazard ratios, which impacts the interpretation of findings. Effect size measures should be included to assess clinical relevance. Data are not fully available, as required by PLOS ONE. The authors should consider depositing the dataset in a public repository.

Language and Clarity: The manuscript contains grammatical errors and inconsistent verb tenses, particularly in the Methods section. A thorough language revision is recommended.

Conclusions: The conclusion that PVC administration is safe should be moderated, as extravasation occurred after 5 days of use. The discussion should clarify potential safe time limits for PVC use.

Overall, this study contributes valuable data to critical care medicine. Addressing these concerns will further strengthen its impact and reliability.

Thank you for your efforts in conducting and sharing this research.

Reviewer #2: Dear Authors,

I do not entirely understand what was your original concept to prove or "rule out". Also, the retrospective manner of the analysis most probably prevented you to reach meaningful comperisons between different patient or procedure groups.

Sincerely

**********

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 10.1371/journal.pone.0333275.r002 Author response to Decision Letter 1 Submission Version 1

9 May 2025

The datasets generated and analyzed during the current study are attached as a separate .xlxs and .dta file format.

Fitsum A. Gemechu, MD

Corresponding Author

Submitted filename: Response to reviewers PLVA.docx

 10.1371/journal.pone.0333275.r003 Decision Letter 1 Sharma Kamal Academic Editor 2025 Kamal Sharma This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 1

4 Jul 2025

PONE-D-25-06871R1Peripheral Line for Vasopressor Administration: Prospective multicenter Observational Cohort study for survival and safetyPLOS ONE

Dear Dr. Assefa Gemechu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Aug 18 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org . When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

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Kamal Sharma

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewer #1: (No Response)

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: No

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This review builds upon my previous comments. While some improvements have been made, key issues remain insufficiently addressed—particularly regarding methodological transparency, statistical rigor, and clarity of presentation.

1. Methodological Concerns: The absence of a control group (e.g., patients receiving vasopressors via central venous catheters) limits the strength of your conclusions. This limitation should be clearly acknowledged and discussed in greater depth. The sample size calculation requires more detailed justification. Please include a formal power analysis to support the adequacy of your study design.

The reported mortality rates (57.6% overall and 67.8% in septic shock) are significantly higher than in comparable studies. Potential confounding variables, such as ICU resource levels, severity scores, or timing of vasopressor initiation, should be addressed or discussed as possible explanations.

2. Statistical Analysis: Confidence intervals are not consistently reported for all hazard ratios, limiting interpretation of statistical precision. No effect size measures (e.g., absolute risk reduction, NNT) are provided, which would help assess the clinical significance of your findings. The proportional hazards assumption is briefly mentioned, but no diagnostic plots or formal outputs (e.g., Schoenfeld residual test results) are included. Consider providing these in supplementary materials.

3. Data Availability: PLOS ONE requires that data underlying the findings be fully available without restriction. Your current statement indicates data are only available upon request due to privacy concerns. Please consider depositing anonymized data in a public repository or provide a stronger justification aligned with journal policy.

4. Language and Clarity: The manuscript contains grammatical errors, awkward phrasing, and inconsistent use of tense, especially in the Methods section. A thorough language revision by a native English speaker or professional editor is strongly recommended.

5. Conclusions and Interpretation: While the study shows a low rate of extravasation (1.2%), all events occurred after prolonged vasopressor use (>5 days). The current conclusion that PVC use is "safe" should be moderated, and a time limit recommendation (e.g., short-term use) should be explicitly discussed. The potential risks of long-term peripheral administration warrant greater emphasis to guide clinicians effectively.

Final Recommendation: Minor Revision

This study has the potential to make a meaningful contribution to the literature on critical care in low-resource environments. However, the above concerns must be addressed to improve the scientific rigor, reproducibility, and clarity of the manuscript.

Thank you again for your efforts in conducting and sharing this important research.

Reviewer #3: All previous comments are accepted. Below is a comment needs attention.

Comment 1: With respect to data availability, authors stated some limitation, please provide reason and which data are not available.

**********

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Reviewer #1: No

Reviewer #3: No

**********

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 10.1371/journal.pone.0333275.r004 Author response to Decision Letter 2 Submission Version 2

16 Aug 2025

Dear Reviewers,

We would like to thank you for your thorough review and constructive feedback on our manuscript. Below, we address each of your comments point by point, indicating the corresponding changes made in the revised manuscript.

Reviewer #1

1.Methodological Concerns: The absence of a control group (e.g., patients receiving vasopressors via central venous catheters) limits the strength of your conclusions. This limitation should be clearly acknowledged and discussed in greater depth. The sample size calculation requires more detailed justification. Please include a formal power analysis to support the adequacy of your study design. The reported mortality rates (57.6% overall and 67.8% in septic shock) are significantly higher than in comparable studies. Potential confounding variables, such as ICU resource levels, severity scores, or timing of vasopressor initiation, should be addressed or discussed as possible explanations.

Response:

�We acknowledge that the lack of a control group (e.g., patients receiving vasopressors via central venous catheters) limits direct comparison and causal interpretation. This limitation is now discussed in greater depth in the revised Limitations of the Study section, along with an explanation that due to severe resource constraints, central venous catheter insertion is rarely performed in our setting. We have also emphasized that this study can serve as a springboard for future randomized controlled trials.

�Regarding the sample size, we have now included a detailed justification and a post-hoc power analysis in the Methods section, indicating a statistical power of 89%, which we consider adequate.

�The higher mortality rates observed (57.6% overall and 67.8% in septic shock) are now explained in the Limitations section, highlighting possible confounding factors such as late presentation, ICU resource limitations, baseline illness severity, and delays in vasopressor initiation.

2. Statistical Analysis: Confidence intervals are not consistently reported for all hazard ratios, limiting interpretation of statistical precision. No effect size measures (e.g., absolute risk reduction, NNT) are provided, which would help assess the clinical significance of your findings. The proportional hazards assumption is briefly mentioned, but no diagnostic plots or formal outputs (e.g., Schoenfeld residual test results) are included. Consider providing these in supplementary materials.

Response:

�We apologize for the oversight. Confidence intervals are now consistently reported for all hazard ratios throughout the manuscript.

�Relative effect size measures such as absolute risk reduction (ARR) and number needed to treat (NNT) could not be calculated due to the absence of a control group.

�We have also included the results of the Schoenfeld residual tests and a summary of the proportional hazards assumption in Table 4, with an expanded explanation in the Statistical Analysis section.

3. Data Availability: PLOS ONE requires that data underlying the findings be fully available without restriction. Your current statement indicates data are only available upon request due to privacy concerns. Please consider depositing anonymized data in a public repository or provide a stronger justification aligned with journal policy.

Response:

�We have updated the Availability of Data and Materials section in accordance with PLOS ONE guidelines. All data generated and analyzed in this study are now publicly available. The de-identified datasets used for analysis can be accessed at the following repository: https://doi.org/10.5281/zenodo.16872086. Additionally, similar datasets in .xlsx and .dta formats are attached to this submission for transparency.

4. Language and Clarity: The manuscript contains grammatical errors, awkward phrasing, and inconsistent use of tense, especially in the Methods section. A thorough language revision by a native English speaker or professional editor is strongly recommended.

Response:

�We acknowledge these language issues. The manuscript has undergone a thorough language revision, focusing particularly on the Methods section, to improve grammar, sentence structure, and clarity.

5.Conclusions and Interpretation: While the study shows a low rate of extravasation (1.2%), all events occurred after prolonged vasopressor use (>5 days). The current conclusion that PVC use is "safe" should be moderated, and a time limit recommendation (e.g., short-term use) should be explicitly discussed. The potential risks of long-term peripheral administration warrant greater emphasis to guide clinicians effectively.

Response:

�We agree with this comment. The Conclusion section has been revised to moderate the safety claim, explicitly recommending PVC use only for short-term vasopressor administration. We have highlighted that while the extravasation rate was low (1.2%), all events occurred after more than five days of use, highlighting the need for caution with prolonged administration.

We believe these revisions address the reviewer’s concerns and strengthen the clarity, rigor, and transparency of our manuscript. We thank you again for your valuable feedback.

Reviewer #3

1.With respect to data availability, authors stated some limitation, please provide reason and which data are not available.

Response:

�As stated above, we have updated the Availability of Data and Materials section in accordance with PLOS ONE guidelines. All data generated and analyzed in this study are now publicly available. The de-identified datasets used for analysis can be accessed at the following repository: https://doi.org/10.5281/zenodo.16872086. Additionally, similar datasets in .xlsx and .dta formats are attached to this submission for transparency.

Sincerely,

Fitsum A. Gemechu, MD

On behalf of all authors

Submitted filename: Response to Reviewers.docx

 10.1371/journal.pone.0333275.r005 Decision Letter 2 Sharma Kamal Academic Editor 2025 Kamal Sharma This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version 2

11 Sep 2025

Peripheral Line for Vasopressor Administration: Prospective multicenter Observational Cohort study for survival and safety

PONE-D-25-06871R2

Dear Dr. Assefa Gemechu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Kamal Sharma

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewer #1:

Reviewer #3:

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: Yes

Reviewer #3: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Thank you for your thoughtful and detailed responses to the previous round of review. I appreciate the improvements you have made to the manuscript, particularly in acknowledging methodological limitations, clarifying the sample size rationale, and strengthening the statistical presentation.

Below is a summary of my assessment of the revised submission:

Methodology and Study Design: The absence of a control group (central venous catheter users) is now more clearly acknowledged and discussed. While this limits causal inference, your clarification improves the transparency of the study design. The sample size justification, based on expected mortality rates and feasibility constraints, is acceptable for an observational cohort study.

2. Mortality and Confounding Factors: The addition of a comparative table and discussion of contextual factors (e.g., ICU capacity, patient severity) provides useful background to interpret the relatively high mortality rates. This section is now more balanced and informative.

3. Statistical Analysis: The inclusion of confidence intervals for hazard ratios improves the interpretability of results. The proportional hazards assumption is addressed, and while no diagnostic plots are provided, the explanation is sufficient for the scope of this study.

4. Data Availability: Shared.

5. Language and Clarity: You state that the manuscript has been revised by a native English speaker. Assuming these edits are reflected in the current version, this issue can be considered resolved.

6. Conclusions: The revised conclusion is appropriately moderated. Emphasizing the safety of PVC use for short-term vasopressor administration, with caution regarding prolonged use, is a fair and evidence-based interpretation of your findings.

Overall, this version of the manuscript reflects substantial improvement and better alignment with scientific reporting standards. Thank you again for your careful attention to reviewer feedback and for contributing this important research.

Reviewer #3: The manuscript titled "Peripheral Line for Vasopressor Administration: Prospective multicenter Observational Cohort study for survival and safety" has now addressed all previous comments. It can be now accepted for publication.

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Reviewer #1: No

Reviewer #3: No

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 10.1371/journal.pone.0333275.r006 Acceptance letter Sharma Kamal Academic Editor 2025 Kamal Sharma This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PONE-D-25-06871R2

PLOS ONE

Dear Dr. Assefa Gemechu,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

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on behalf of

Dr. Kamal Sharma

Academic Editor

PLOS ONE