Risk Factors for Serious Hypotension Induced by Intravenous Acetaminophen in Patients With Hematologic Malignancy.

Summary

Three risk factors for the occurrence serious hypotension due to intravenous acetaminophen administration during fever were derived from patients with hematologic malignancies: high pre‐administration body temperature (°C), acute kidney injury, and bacteremia.

A higher mean arterial pressure, prior to intravenous acetaminophen administration, indicated less serious hypotension.

Escherichia coli was the most common Gram‐negative bacterium while Staphylococcus species were the most common Gram‐positive bacteria that caused bacteremia in hematologic malignancy patients.

Continuous monitoring of hypotension is required when administering acetaminophen intravenously in patients with hematologic malignancy and these associated risk factors.

Introduction

Injectable forms of antipyretic analgesics such as acetaminophen (AAP) provide more rapid relief compared with their oral equivalents. Additionally, owing to their predictable pharmacokinetic properties, injectable antipyretics are widely used in critically ill patients who cannot be administered oral antipyretics [ 1 , 2 ].

In Korea, AAP injections were approved in 2017, and their utilization increased following the implementation of the National Narcotics Information Management System in May 2018. This surge in usage was coincident with the release of the American Medical Association's pain management guidelines for adult intensive care patients in September 2018, which recommended to consider the use of non‐narcotic analgesics such as AAP and nefopam because of the adverse effects associated with narcotics application [ 3 ].

The incidence of hypotension listed in domestic permits is between 0.01% and 0.1% [ 4 ]. However, in a study of critically ill patients, 51.9% of the patients experienced hypotension following intravenous administration of AAP, with 34.9% of them requiring therapeutic intervention for critical hypotension [ 5 ]. This raises ongoing safety concerns regarding the low blood pressure of intravenous AAP administration [ 6 , 7 ]. Hypotension can lead to fatal consequences due to insufficient myocardial perfusion. Previous research has indicated that adverse effects of hypotension have harmful effects such as increased mortality and decreased physiological function, necessitating close monitoring [ 8 ].

Patients with hematologic malignancies exhibit heightened susceptibility to hemodynamic instability due to various factors, including hemorrhage, tumor lysis syndrome, and fluid imbalance during chemotherapy [ 9 , 10 ]. Furthermore, these patients are particularly vulnerable to infections, which can escalate to sepsis and lead to septic shock, characterized by vasodilation and a rapid decline in blood pressure [ 11 , 12 ]. Septic shock can have a devastating impact on multiple organ systems. A study by Manjappachar et al. [ 13 ] suggested the need for interventions such as early admission to the intensive care unit (ICU), administration of aminoglycosides, and treatment with granulocyte colony stimulating factor , as septic shock in patients with hematologic malignancies remains associated with a high mortality rate and poor 90‐day survival outcomes.

A review by Maxwell et al. [ 14 ], which analyzed 19 articles, found no significant correlation between hypotension and factors such as product formulation, injection rate, or total dosage. Instead, the risk and incidence of hypotension may be attributed to specific patient characteristics including age and baseline blood pressure. However, the currently known risk factors have not yield consistent findings across various studies [ 5 , 7 , 14 , 15 ]. Therefore, the present study aimed to evaluate the risk factors and prognosis of serious hypotension caused by intravenous AAP administration during febrile episodes in patients with hematologic malignancies, using electronic medical records and in‐hospital adverse drug reaction (ADR) reports.

Methods

Study Subjects

We conducted a retrospective case–control study, which included case reports of ADRs due to intravenous AAP administration at a regional drug safety center in a tertiary hospital from January 1, 2023, to December 31, 2023. We included hospitalized patients who were evaluated for serious hypotension as an ADR corresponding to Common Termination Criteria for Advertising Events (CTCAE) Version 5.0 criteria Grades 3–5 (Grade 1: asymptomatic, intervention not indicated; Grade 2: non‐urgent medical intervention indicated; Grade 3: medical intervention and hospitalization indicated; Grade 4: life‐threatening consequences and urgent intervention indicated; Grade 5: death). Cases evaluated as certain, probable/likely, and possible based on the WHO‐UMC causality assessment were included. Among the patients reported with serious hypotension, we included those with hematologic malignancies who received intravenous AAP. Patients under the age of 18 years or those already in the intensive care unit or hospice hospital before intravenous AAP administration were excluded. The control group consisted of three matched patients with hematologic malignancies who also received intravenous AAP during the same period but did not report hypotension, matched by age and sex. The selected control group was confirmed through an electronic medical records (EMR) review to have not experienced hypotension during the hospitalization period when intravenous AAP was administered. Sex was matched, and ages were paired within a range of 0 to ±2 years (Figure 1 ).

Covariates

The basic characteristics of the patients, including age, sex, height, weight, medical department, chief complaint, disease name, and underlying disease at the time of hospitalization, were obtained from EMR. As clinical variables, systolic and diastolic blood pressure at hospitalization, systolic and diastolic blood pressure before intravenous AAP administration, body temperature, neutropenic fever, graft‐versus‐host disease (GVHD), bacteremia, sepsis, septic shock, and sepsis shock after intravenous AAP administration were collected. Regarding drug‐use history, we investigated whether previous oral antipyretics were taken, whether previous intravenous antipyretics were administered (a non‐AAP injection), the dose of AAP, the frequency of repeated administrations, and the concurrent medications used were investigated. Concurrent medications included hypotensive drugs with narcotic analgesics, antiviral drugs, and antifungal drugs that may influence blood pressure. For the serious hypotension group, drug administration was investigated based on medications given from 5 days prior to the onset of abnormal symptoms to the onset of those symptoms. In contrast, for the control group, the period from 5 days before the final point of repeated intravenous AAP administration at the time of fever to the final point was monitored. As infection‐related variables, culture test results and infection sites were investigated. Additionally, treatment after serious hypotension, such as fluid bolus, norepinephrine, and vasopressor (other than norepinephrine) administration; leg elevation; and intensive care unit admission were checked. The information of length of hospital stay and 90‐day mortality were collected as clinical outcomes. The variables investigated in the study was shown in Figure 2 .

Statistical Analysis

For continuous variables, an independent t ‐test or Mann–Whitney U test was used after assessing the normality of the distribution using the Shapiro–Wilk test. For categorical variables, the chi‐square test or Fisher's exact test was used. Multivariable logistic regression analysis was performed after confirming independence through Pearson correlation analysis and variance inflation factor (VIF) analysis, except for the items in which the control group had a value of “0” among variables that exhibited a p ‐value of less than 0.05 in univariable analysis. A value of p < 0.05 was considered statistically significant. The statistical analyses were performed using IBM SPSS Statistics for Windows, Version 28.0 (released in 2021; IBM Corp., Armonk, NY, USA).

This study was a retrospective investigation conducted using EMR inquiries at a single tertiary hospital. It was reviewed by the Seoul St. Mary's Hospital Data Review Board (DRB) and approved as a deliberation exemption (task number: 20240612‐023). Additionally, this study was approved by the Institutional Review Board (IRB) of St. Mary's Hospital (KC24RISI0446/2024‐1598‐0001) and informed consent was not obtained, as the study met the criteria for exemption.

Results

Subject Characteristics

A total of 148 patients participated in this study, comprising 37 serious hypotension group patients and 111 control group. The age range of patients in the case group was 21–78 years with a median age of 61, while the control group had an age range of 21–80 years with a median age of 60. In the serious hypotension group, the most prevalent condition is acute myeloid leukemia (40.5%), followed by acute lymphocytic leukemia (32.4%) and multiple myeloma (13.5%). In the control group, acute myeloid leukemia (29.7%) was the most frequently observed disease, followed by multiple myeloma (19.8%) and lymphoma (17.1%). Furthermore, 20 patients in the serious hypotension group received chemotherapy (54.1%), while 11 patients (29.7%) underwent some other interventions, and 6 patients (16.2%) received hematopoietic stem cell transplantation (HSCT). In contrast, in the control group, 47 patients (42.3%) received other interventions, 39 (35.1%) underwent HSCT, and 25 patients (22.5%) received chemotherapy (Table 1 ).

Risk Factors

As a result of univariable analysis of clinical variables and concurrent medications of the two groups, significant differences were observed in six items: mean arterial pressure (MAP) prior to administration (mmHg) ( p = 0.010), body temperature prior to administration (°C) ( p < 0.001), acute kidney injury (AKI) ( p = 0.018), neutropenic fever ( p = 0.012), bacteremia ( p < 0.001), and beta blocker ( p = 0.046). The other characteristics did not show significant differences between the two groups (Tables 2 and 3 ).

Pearson correlation analysis revealed that the correlation coefficients for MAP prior to administration (mmHg), pre‐treatment body temperature (°C), AKI, neutropenic fever, bacteremia, and the use of beta‐blockers ranged from −0.17 to 0.29, with VIF of less than 1.2. This indicates independence among the variables. Multivariate regression analysis showed that pre‐administration body temperature, AKI, and bacteremia had odds ratio of 9.81 (95% CI 3.49–27.53, p < 0.001), 14.99 (95% CI 3.13–71.87, p < 0.001), and 6.36 (95% CI 2.01–20.11, p = 0.002), respectively. MAP prior to administration was found to reduce the risk of serious hypotension with an increase of 1 mmHg (OR 0.96, 95% CI 0.92–1.00, p = 0.049) (Table 4 ).

Analysis of Microbial Infections

In the case of the microbial infection analysis, the case where the culture result was positive was analyzed, not based on the number of patients. Therefore, there is no overlap of patients, but in the culture test, there may be overlap of the infection site and the causative bacteria in one patient.

The site of infection was observed as 42 sites in the serious hypotension group, including overlapping infections, and 51 sites in the control group, and 30 strains were identified in the serious hypotension group, including overlapping infections, and 51 strains in the control group.

In the microbiologically confirmed infection, in the serious hypotension group, bacteremia and central venous catheter infection were common, and bacteremia and respiratory infection were common in the control group. Bacteremia and central venous catheter infection were significantly higher in the serious hypotension group, respectively ( p < 0.001, p = 0.001, Table 5 ).

It is confirmed that Gram‐negative bacterial infections are much more common in the serious hypotension group than in the control group ( p < 0.001). As a result of subgroup analysis, Escherichia coli is the most common causative agent and is 4.08 times more common in the serious hypotension group than in the control group ( p < 0.018). Among the Gram‐positive bacteria, Staphylococcus is the most common causative agent and is 6.97 times more common in the serious hypotension group than in the control group ( p = 0.008) (Table 6 ).

Outcomes

Among the serious hypotension group, 24 patients (64.9%) developed septic shock, and the average duration of hypotension was 11.3 ± 13.7 h. After serious hypotension, 36 cases (97.3%), 32 (86.5%), and 24 (64.9%) received norepinephrine administration, fluid bolus, and leg elevation treatment, respectively. Additionally, 8 cases (21.6%) required increased norepinephrine administration, 3 (8.1%) received vasopressor administration in addition to norepinephrine, and 6 (16.2%) were transferred to intensive care units (ICU) (Figure 3 ).

There was no significant difference in the length of hospitalization between the two groups (on average 40.4 ± 23.0 vs. 35.1 ± 30.0 days, p = 0.331) when comparing the outcomes of the serious hypotension group with those of the control group. The 90‐day mortality rate was higher in the serious hypotension group, but the difference was not statistically significant (27.0% vs. 14.5%; p = 0.090) (Table 7 ).

Discussion

In this study, three independent risk factors for serious hypotension were identified: elevated pre‐administration body temperature (°C), AKI, and bacteremia. Additionally, a higher MAP prior to administration was associated with reduced risk of developing serious hypotension, suggesting its potential role as a protective factor.

The median body temperature of the serious hypotension group was 38.9°C ± 0.6°C, while that of the control group was 38.3°C ± 0.5°C. These findings are consistent with the results of an observational study conducted on patients in the ICU for neurological conditions [ 15 ], and a study of patients with urinary tract infections in the emergency room also reported that a high fever of 39°C or higher was associated with continuous hypotension after intravenous AAP administration [ 16 ]. Recent studies have highlighted the following for fever in hematologic malignancies. Fever is a common manifestation of infectious and noninfectious syndromes after HSCT and CAR‐T therapy. Empiric antibiotics should be administered for febrile neutropenia, though they can be stopped or modified once the fever resolves. While antibiotics are also indicated in febrile patients with sepsis, clinical instability, or asplenia, they should be discontinued when an infection is ruled out [ 17 ].

The proportion of patients with AKI as an underlying disease was 7 out of 37 (18.9%) in the serious hypotension group and 7 out of 111 (6.3%) in the control group. Additionally, the proportion of patients with AKI as an underlying disease was notably higher in the serious hypotension group.

Considering the pharmacokinetic characteristics of AAP, which is mainly excreted through the kidneys [ 4 ], it is estimated that the delays in renal excretion in patients with AKI contribute to an increased incidence of adverse effects. This observation aligns with suggestions from some studies that the mechanism of action of hypotension associated with AAP is related to its pharmacokinetic characteristics rather than hypersensitivity [ 18 ]. However, caution should be taken in interpretation because AKI may be caused by bacteremia, and serious hypotension may have occurred as a result.

As a result of the study, bacteremia was found to be a significant risk factor, increasing the likelihood of serious hypotension by 7.26 times. This finding is consistent with previous studies by Kwack et al. [ 19 ], which suggested that when propacetamol is administered to patients visiting the emergency room with various symptoms accompanied by fever, blood pressure is likely to decrease if hs‐CRP levels exceed 11.86 mg/L or if procalcitonin levels are higher than 0.67 ng/mL. In previous studies, septic shock was reported as a risk factor for hypotension induced by intravenous AAP administration [ 18 ]. However, in this study, there were 6 patients in the serious hypotension group, and statistical significance was not obtained as none of them were reported in the control group.

As a result of subgroup analysis of microbiologically confirmed infections, E. coli was the most common causative agent, which was significantly more common in the serious hypotension group than in the control group, and Staphylococcus was the most common causative agent among Gram‐positive bacteria, which was significantly more common in the serious hypotension group than in the control group by 6.97 times. This is similar to the content of the separation of Gram‐negative bacteria, Gram‐positive bacteria, and fungi, respectively, in the bacteremia study of pediatric blood tumor patients, and this study suggested that Gram‐negative bacteria are a common causative agent of bacteremia in pediatric tumor patients and are highly related to poor prognosis [ 20 ].

The median MAP before administration in the serious hypotension group was 86.7 (63–140), and the median MAP before administration in the control group was 96.3 (71–149). This indicates a significantly lower MAP prior to administration in the serious hypotension group. Furthermore, an increase of 1 mmHg in MAP prior to administration was associated with a 0.96‐fold reduction in the risk of serious hypotension. In this study, blood pressure at the time of hospitalization and MAP prior to administration are analyzed separately. However, it is important to note that blood pressure at hospitalization may not accurately reflect the patient's condition during fever. Therefore, it may be more appropriate to consider MAP before administration as the baseline blood pressure, representing the patient's state prior to intravenous AAP administration. In previous reports concerning baseline blood pressure, various measurements such as baseline systolic blood pressure (SBP) and baseline MAP have been used, and their associations have been reported [ 15 , 16 , 21 ]. Regarding baseline MAP, some research has reported that both low and high SBP, excluding normal levels, are correlated with hypotension following intravenous AAP administration [ 15 ]. In addition, several studies have shown that the hypotension group exhibited significantly higher baseline SBP and diastolic blood pressure as well as elevated baseline body temperature in comparison to the non‐hypotension group. Although the underlying mechanism of this opinion is not fully elucidated, it is thought that the exothermic response stimulates the sympathetic nervous system, leading to vasoconstriction. Furthermore, it has been suggested that the antipyretic action of propacetamol significantly reduces sympathetic nervous activity, resulting in relaxation, a reduction of heart rate, and hypotension [ 16 ]. It is estimated that a higher level of baseline blood pressure within the normal range mitigates hypotension; however, in cases of high blood pressure caused by fever, the antipyretic effect can lead to a sharp decrease in blood pressure.

The number of previous antipyretic administrations (both oral and intravenous), and the frequency of intravenous AAP administration did not significantly affect the occurrence of serious hypotension. Additionally, the use of vasopressors, antihypertensive medications, sedatives, and narcotic analgesics were not found to be significant. However, beta‐blockers emerged as a significant factor in the univariable analysis, warranting caution due to the potential impact of reduced cardiac output associated with their use. In some studies, since acetaminophen has been reported to reduce cardiac output [ 22 , 23 ], it was suggested that hypotension observed in heart failure patients using beta‐blockers may be associated with decreased cardiac output due to acetaminophen, but the mechanism of the effect of acetaminophen on cardiac output is not yet clear. Although this study did not reveal any correlation with co‐treatment drugs, Lee et al. [ 15 ] found that IV propacetamol reduced both cardiac output and systemic vascular resistance, allowing blood pressure to be lowered in a hemodynamically unstable state, so patients receiving vasopressors/inotropes were more vulnerable to blood pressure drop. Also, patients who received analgesics/sedatives were also vulnerable to blood pressure drop. These drugs reduce vascular resistance, cause vasodilation, stimulate pre‐synaptic α‐2a receptors, or inhibit the sympathetic nervous system, causing hypotension [ 24 , 25 , 26 ]. Therefore, BP drop events are more likely to occur because of the synergistic effects of coadministering analgesics/sedatives and propacetamol [ 15 ]. Therefore, close monitoring is also necessary when administering co‐treatments that can cause hypotension during intravenous AAP.

When evaluating the clinical outcomes of the serious hypotension group compared to the control group, the 90‐day mortality rate in the hypotension group was higher, but it was not statistically significant. The extent to which serious hypotension resulting from intravenous AAP contributes to mortality remains unclear in this study, indicating a need for further research. There was no significant difference in hospitalization durations between the two groups, and it cannot be ruled out that the mortality in the serious hypotension group could have shortened the average hospitalization period.

The mechanisms of developing low blood pressure due to intravenous AAP administration was not clearly identified in this study. Hersch et al. [ 27 ] suggested failure to control vascular tension may be a cause of hypotension. Boyle et al. [ 28 ] reported increased skin blood flow resulting from decreased peripheral vascular resistance. Kwack et al. [ 19 ] indicated when infection‐related factors are high, blood pressure is likely to decrease. Chiam et al. [ 29 ] showed that a decrease in systemic vascular resistance index was correlated with the occurrence of hypotension. A recent study suggests that both direct and indirect activation of the Kv7 channel by N‐acetyl‐p‐benzoquinone imine (NAPQI), a metabolite of AAP/paracetamol, can reduce arterial tone, thereby lowering blood pressure [ 30 ]. Another recent research highlighted the significant role of elevated myeloperoxidase (MPO) in the endothelium of critically ill patients. In these patients, increased MPO facilitates the conversion of AAP to NAPQI after intravenous administration, occurring in the endothelium rather than the liver. The rise of NAPQI may contribute to the hypotension mechanism by promoting the release of calcitonin gene‐related peptide, a potent vasodilator [ 31 ]. Therefore, the mechanism leading to serious hypotension in patients with reduced peripheral vascular resistance due to infection and bacteremia fails to address the hypotension caused by intravenous AAP administration. This suggests a risk of septic shock during bacteremia when administering acetaminophen intravenously in febrile conditions, such as neutropenic fever, which is common in patients with hematologic malignancies. Additionally, intravenous AAP administration may directly induce hypotension in critically ill patients by facilitating the metabolism of AAP in the endothelium.

This study has some limitations. Although all potential risk factors were investigated in this study, we could match only age and sex between the patient and control groups. Additionally, patients with acute lymphoblastic leukemia (ALL), patients with lymphoma, patients undergoing chemotherapy, and patients with HSCT were significantly different between both groups: the serious hypotension group had a higher proportion of ALL and chemotherapy patients, while lymphoma and HSCT patients with relatively good condition were higher in the control group.

This study retrospectively reviewed electronic medical records based on adverse event reports, defined as serious hypotension by health care professionals, to identify the current status of serious hypotension resulting from intravenous AAP in patients with hematologic malignancies and to derive significant risk factors associated with the occurrence of serious hypotension. In conclusion, elevated pre‐administration body temperature (°C) (OR 9.81), acute kidney injury (OR 14.99), and bacteremia (OR 6.36) were found to independently increase the incidence of serious hypotension, while a high MAP prior to administration (OR 0.96) was associated with a decreased incidence of serious hypotension. Close monitoring of adverse events related to serious hypotension is required when administering AAP intravenously to patients with hematologic malignancies who present these significant risk factors. Furthermore, there is a need for future research to identify biomarkers associated with the occurrence of hypotension during intravenous AAP administration.

Plain Language Summary

Critically ill patients who have difficulty using oral antipyretics are often administered acetaminophen (AAP) intravenously due to its rapid antipyretic effects and predictable pharmacokinetic properties. However, previous studies have indicated the risk of developing hypotension as a result of intravenous AAP administration in these patients. We aimed to address this issue by conducting a retrospective case–control study that included patients with hematologic malignancies and who developed adverse drug reactions (ADRs) following intravenous AAP administration. This study identified three risk factors associated with the occurrence of serious hypotension due to intravenous AAP during fever in patients with hematologic malignancies: high pre‐administration body temperature (°C), acute kidney injury, and bacteremia. A higher mean arterial pressure prior to intravenous administration of AAP, as a protective indicator, was associated with a lower incidence of serious hypotension. E. coli was the most common Gram‐negative bacterium, while Staphylococcus species were the most prevalent Gram‐positive bacteria causing bacteremia in patients with hematologic malignancies. Continuous monitoring for hypotension is essential when administering acetaminophen intravenously in patients with hematologic malignancies, particularly in the presence of these associated risk factors.

Ethics Statement

This study was approved by the Institutional Review Board (IRB) of St. Mary's Hospital (KC24RISI0446/2024‐1598‐0001).

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

This research was supported by a grant (RS‑2023‑00217123) from the National Research Foundation of Korea (NRF). We also thank the Department of Pharmacy at Seoul St. Mary’s Hospital, as well as the Ministry of Food and Drug Safety and the Korea Institute of Drug Safety and Risk Management, for their support

Funding: This research was funded by a grant (RS‐2023‐00217123) from the National Research Foundation of Korea (NRF).

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