Risk Factor of Persistent Hypotension Associated with 5-Aminolevulinic Acid: A Single-Institution Retrospective Study

Abstract

5-Aminolevulinic acid (5-ALA), an amino acid precursor of protoporphyrin IX, is used in the photodynamic diagnosis (PDD) of bladder cancer because it emits fluorescence at specific wavelengths. Severe hypotension has been reported in patients undergoing 5-ALA-based PDD. Previous studies have mainly focused on hypotension occurring immediately after 5-ALA administration. Persistent hypotension lasting beyond the day of administration has also been reported, indicating a need for continued postoperative management. However, the risk factors associated with persistent 5-ALA-induced hypotension remain unclear. This retrospective study aimed to identify the risk factors for persistent hypotension following 5-ALA administration. Among 263 patients who received 5-ALA for PDD of bladder cancer at Yamaguchi University Hospital between April 2018 and March 2022, 183 developed hypotension and were included in the analysis. Patients were classified into a persistent hypotension group (n = 30), comprising those with continued hypotension the following day, and a nonpersistent group (n = 153). Baseline demographics and clinical characteristics were comparable between the groups. In contrast, preoperative hemoglobin levels were significantly lower in the persistent group (p < 0.05). Multivariate logistic regression analysis identified preoperative hemoglobin levels as an independent risk factor for persistent hypotension (odds ratio, 0.76; 95% confidence interval, 0.60–0.97). A hemoglobin concentration of 12.9 g/dL was determined as the cutoff value for predicting the incidence of persistent hypotension using receiver-operating characteristic curve analysis. Although further validation is required, these findings suggest that the preoperative hemoglobin level may serve as a potential indicator for risk stratification of persistent hypotension induced by 5-ALA.

INTRODUCTION

5-Aminolevulinic acid (5-ALA) is an amino acid precursor of protoporphyrin IX (PpIX). After administration, 5-ALA is absorbed and metabolized to PpIX in the mitochondria. In normal cells, PpIX is converted to heme through iron incorporation catalyzed by ferrochelatase (FECH). However, in tumor cells, FECH activity is often relatively low, resulting in intracellular accumulation of PpIX.¹⁾ PpIX functions as a photosensitizer that emits red fluorescence (600–740 nm) upon excitation with blue light (375–445 nm).²⁾ Based on this mechanism, photodynamic diagnosis (PDD) using 5-ALA has been widely used for the management of bladder cancer. A multicenter phase III study in Japan demonstrated the feasibility of using ALA-PDD for bladder cancer, with 79.6% sensitivity and 80.6% specificity.³⁾ This technique improves complete tumor resection rates and reduces the risk of recurrence.^4,5)

In addition to other common adverse events, such as elevated liver enzyme levels and gastrointestinal symptoms, including nausea and vomiting,^6,7) hypotension is reportedly one of the most frequent adverse effects of 5-ALA. Although the incidence of hypotension has been low in clinical trials, real-world studies have reported rates ranging from 6 to 70%,^3,8–10) reflecting heterogeneous definitions, perioperative timing, and anesthetic practices. Moreover, several case reports have described severe hypotension occurring in the perioperative period after taking 5-ALA,^11,12) suggesting that hypotension is a clinically significant adverse event that requires appropriate perioperative management. Although the pathophysiological mechanism underlying 5-ALA-induced hypotension remains unclear, vasodilation via PpIX-mediated activation of soluble guanylate cyclase has been proposed.¹³⁾ Following oral administration of 5-ALA at standard doses, plasma PpIX levels peaked within 4 h, declined rapidly thereafter, and became undetectable within 48 h.¹⁴⁾ Accordingly, clinical attention has traditionally been focused on intraoperative hypotension. However, persistent hypotension extending beyond the immediate postoperative period has been reported in patients with end-stage renal disease, potentially due to the delayed elimination of 5-ALA or its metabolites.¹⁵⁾ Persistent hypotension after 5-ALA administration has been observed in a subset of patients,¹⁶⁾ indicating the need for extended hemodynamic monitoring beyond the intraoperative period. Nonetheless, little attention has been paid to prolonged hypotension following 5-ALA administration, and the patient characteristics and risk factors associated with its persistence remain unclear.

This retrospective study aimed to identify the clinical features associated with persistent hypotension following 5-ALA administration.

PATIENTS AND METHODS

Patient Selection

This single-center observational study included 266 patients with bladder cancer who were prescribed 5-ALA between April 1, 2018, and March 31, 2022, at Yamaguchi University Hospital (Yamaguchi Prefecture, Japan) and who underwent transurethral resection of the bladder tumor (TURBT). Patients who were prescribed 5-ALA but did not receive it were excluded from the study (n = 3). All patients received an oral dose of 20 mg/kg 5-ALA 2–3 h prior to TURBT. The method of anesthesia induction and the use of intraoperative vasopressors were determined at the discretion of the attending anesthesiologist. Patients who developed hypotension on the day of 5-ALA administration were included in this analysis. Hypotension on the day of administration was defined as a systolic blood pressure (SBP) <80 mmHg during surgery⁹⁾ or SBP <100 mmHg postoperatively on the same calendar day.¹⁷⁾ If the lowest SBP of <100 mmHg was recorded on the next day after surgery, the patient was considered to have persistent hypotension. Postoperative blood pressure was routinely measured approximately 3 times per day, with additional measurements taken when necessary. To classify persistent hypotension, the lowest blood pressure recorded during the day was used, without accounting for diurnal variation to maximize sensitivity for detection. The patients were then categorized into persistent and nonpersistent hypotension groups.

Data Collection

Baseline patient data at the time of admission, including sex, age, body weight, hematocrit, hemoglobin, serum creatinine, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels, prior treatment history, and the lowest SBP recorded on the day of admission, were retrospectively extracted from the electronic medical records. The number and type of antihypertensive medications, use of general anesthesia, and estimated glomerular filtration rate (eGFR), all previously reported risk factors for intraoperative hypotension following 5-ALA administration,^{8–10,18,19)} were also extracted. Antihypertensive medications included angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, diuretics, and beta-blockers. Preoperative discontinuation of antihypertensive medications was at the discretion of the attending physician. If discontinued, administration was withheld on the day of surgery and resumed the following day. The eGFR was calculated using an established formula (equation for eGFR in Japanese²⁰⁾). Data on intraoperative vasopressor use, lowest intraoperative SBP, duration of surgery and anesthesia, and blood loss during surgery were extracted from the surgical records.

Statistical Analysis

Categorical variables were presented as numbers and percentages, and comparisons between groups were performed using Fisher’s exact test. Continuous variables were shown as medians with interquartile ranges (IQR), and differences were assessed using the Mann–Whitney U-test. Correlations between continuous variables were assessed using Pearson’s correlation coefficient. Univariate and multivariate logistic regression analyses were performed to identify the risk factors associated with persistent hypotension. To enable the flexible selection of explanatory variables in the multivariate model, we first performed univariate logistic regression analyses using baseline characteristics and previously reported risk factors for intraoperative hypotension following 5-ALA administration as candidate variables. Variables with a p-value <0.1 in the univariate analyses were selected as independent variables for the multivariate model. When the correlation coefficient between 2 candidate variables exceeded 0.9, the variable with the smaller p-value in the univariate analysis was retained to avoid multicollinearity. In another model, the independent variables included age, number of antihypertensive medications, general anesthesia use, and eGFR, which were previously reported as risk factors for intraoperative hypotension following 5-ALA administration,^{8–10,18,19)} as well as variables showing significant differences between groups. The selected variables were then entered into the model using the forced-entry method. For variables identified as statistically significant in the logistic regression analysis, a receiver-operating characteristic (ROC) curve analysis was conducted to determine the cutoff values for predicting the incidence of persistent hypotension. Statistical significance was set at a 2-sided p-value <0.05. All analyses were performed using the JMP^® Pro version 16 (SAS Institute, Cary, NC, U.S.A.).

Ethical Approval Statement

The study protocol was approved by the Yamaguchi University Hospital Ethics Committee (Ethics Committee Registration Number: H2024-077) and was conducted in accordance with stipulations on the handling of patients’ personal information. The requirement for informed consent was waived owing to the retrospective nature of this study.

RESULTS

Patient Characteristics

A flowchart of patient selection for this study is presented in Fig. 1. Of the 263 patients who received 5-ALA, 183 (69.5%) developed hypotension after 5-ALA administration and were included in the analysis. Among them, 30 were classified into the persistent hypotension group and 153 into the nonpersistent hypotension group. There were no significant differences between the 2 groups in terms of sex, age, body weight, serum creatinine, AST, or ALT levels, eGFR, number or type of antihypertensive medications, or history of prior treatment (Table 1). However, preoperative hemoglobin levels (persistent hypotension group: median, 12.7 g/dL; IQR, 11.7–13.8 g/dL; nonpersistent group: median, 13.5 g/dL; IQR, 11.4–14.7 g/dL; p < 0.05), with an absolute median difference of 0.9 g/dL, and hematocrit (persistent hypotension group: median, 37.9%; IQR, 35.6–40.7%; nonpersistent group: median, 39.9%; IQR, 37.8–43.4%; p < 0.05), with an absolute median difference of 2.0%, were significantly different between the 2 groups. The correlation coefficient between hemoglobin and hematocrit was 0.96 (95% confidence interval [CI], 0.94–0.97). The baseline SBP at admission was 123 mmHg (IQR, 111–133 mmHg) in the persistent group and 126 mmHg (IQR, 115–151 mmHg) in the nonpersistent group, with no significant differences. The use of general anesthesia and intraoperative vasopressors, duration of surgery and anesthesia, and lowest intraoperative SBP values were also comparable between the groups. Among patients with intraoperative blood loss recorded as 0 mL, 27 (90%) were in the persistent hypotension group and 142 (93%) were in the nonpersistent group. Only 1 patient in each group experienced blood loss >10 mL. SBP on the next day after surgery was significantly lower in the persistent hypotension group (median, 95 mmHg; IQR, 92–98 mmHg) than in the nonpersistent group (median, 113 mmHg; IQR, 105–128 mmHg; p < 0.01).

Fig. 1. Study Flowchart

Patients who developed hypotension after 5-ALA administration were classified based on the presence (n = 30) or absence (n = 153) of persistent hypotension on the following day. 5-ALA: 5-aminolevulinic acid.

Table 1. Patient Characteristics

Parameter	Persistent hypotension (n = 30)	Nonpersistent hypotension (n = 153)	p-Value
Male (%)	24 (80.0)	123 (80.4)	1.00a)
Age (years)	75.0 (69.0–80.0)	75.0 (68.8–82.3)	0.81b)
Body weight (kg)	61.7 (50.5–67.0)	62.8 (54.6–79.2)	0.29b)
Hemoglobin (g/dL)	12.7 (11.7–13.8)	13.5 (11.4–14.7)	0.02b)
Hematocrit (%)	37.9 (35.6–40.7)	39.9 (37.8–43.4)	0.015b)
Creatinine (mg/dL)	0.97 (0.79–1.13)	0.92 (0.76–1.07)	0.29b)
eGFR (mL/min/1.73 m2)	56.6 (49.2–66.2)	59.4 (48.9–68.7)	0.45b)
AST (IU/L)	21.0 (18.8–27.3)	21.0 (18.0–27.0)	0.45b)
ALT (IU/L)	18.5 (13.0–26.3)	17.0 (13.0–25.0)	0.57b)
Number of antihypertensive drugs	1 (0–2)	1 (0–2)	0.19b)
Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers	9 (30.0)	68 (44.4)	0.16a)
Calcium channel blockers	10 (33.3)	79 (51.6)	0.075a)
Diuretics	1 (3.3)	13 (8.5)	0.47a)
Beta-blockers	7 (23.3)	28 (18.3)	0.61a)
Treatment history
TURBT (%)	7 (23.3)	31 (20.3)	0.14a)
Intravesical BCG (%)	6 (20.0)	15 (9.8)	0.12a)
Chemotherapy (%)	1 (3.3)	7 (4.8)	1.00a)
Systolic blood pressure at admission (mmHg)	123 (111–133)	126 (115–151)	0.13b)
Use of general anesthesia (%)	21 (70)	93 (60.8)	0.41a)
Use of vasopressors during surgery (%)	27 (90.0)	147 (96.1)	0.17a)
Duration of surgery (min)	72 (42–92)	66 (46–95)	0.58b)
Duration of anesthesia (min)	123 (90–164)	116 (84–154)	0.72b)
Lowest systolic blood pressure during surgery (mmHg)	70 (65–77)	71 (65–76)	0.96b)
Lowest systolic blood pressure one day after surgery (mmHg)	95 (92–98)	113 (105–128)	<0.01b)

Data are presented as number (%) or median (interquartile range). a) Fisher’s exact test. b) Mann–Whitney U-test. eGFR: estimated glomerular filtration rate; AST: aspartate aminotransferase; ALT: alanine aminotransferase; TURBT: transurethral resection of bladder tumor; BCG: Bacillus Calmette–Guerrin.

Identification of Risk Factors for Persistent Hypotension Induced by 5-ALA

To select variables for the multivariate logistic regression model, baseline characteristics and previously reported risk factors for intraoperative hypotension associated with 5-ALA administration, including age, number of antihypertensive medications, use of general anesthesia, and eGFR, were first applied to the univariate logistic analysis. Therefore, preoperative hemoglobin, hematocrit, and SBP at admission were identified as candidate variables for the multivariate model. Because hemoglobin and hematocrit were strongly correlated, hemoglobin, which had the smaller p-value in the univariate analysis, was retained for inclusion in the multivariate model. In the multivariate logistic model, a lower preoperative hemoglobin level was significantly associated with persistent hypotension (odds ratio, 0.76; 95% CI, 0.60–0.97; p = 0.025) (Table 2). In another multivariate logistic model, which included variables previously reported as risk factors for intraoperative hypotension following 5-ALA administration, the same result was observed (odds ratio, 0.78; 95% CI, 0.61–0.99; p = 0.044).

Table 2. Multivariate Logistic Regression Analysis for Persistent Hypotension

Parameters	Univariate analysis			Multivariate analysisa)			Multivariate analysis with another modelb)
	OR	95% CI	p-Value	OR	95% CI	p-Value	OR	95% CI	p-Value
Male	1.03	0.39–2.73	0.96	—	—	—	—	—	—
Age	0.99	0.96–1.03	0.77	—	—	—	0.98	0.94–1.03	0.44
Body weight	0.98	0.95–1.01	0.21	—	—	—	—	—	—
Hemoglobin	0.76	0.60–0.95	0.019	0.76	0.60–0.97	0.025*	0.78	0.61–0.99	0.044*
Hematocritc)	0.91	0.83–0.99	0.033	—	—	—	—	—	—
eGFR	0.99	0.96–1.01	0.24	—	—	—	0.99	0.96–1.01	0.27
ALT	1.01	0.99–1.03	0.26	—	—	—	—	—	—
AST	1.01	0.99–1.04	0.26	—	—	—	—	—	—
Number of antihypertensive drugs	0.81	0.57–1.15	0.24	—	—	—	0.83	0.57–1.21	0.34
Systolic blood pressure at admissiona)	0.98	0.95–1.00	0.065	0.98	0.95–1.00	0.088	—	—	—
Use of general anesthesia	1.51	0.65–3.51	0.34	—	—	—	1.50	0.63–3.60	0.37
Use of vasopressors during surgery	0.38	0.089–1.56	0.17	—	—	—	—	—	—
Duration of surgery (min)	1.00	0.99–1.01	0.50	—	—	—	—	—	—
Duration of anesthesia (min)	1.00	0.99–1.01	0.85	—	—	—	—	—	—

Odds ratio for continuous variables represent the change in odds ratio per one-unit increase in each parameter. a) Independent variables in this model included hemoglobin and systolic blood pressure at admission. b) Independent variables in this model included age, hemoglobin, eGFR, number of antihypertensive drugs and use of general anesthesia. c) Because hematocrit showed a strong correlation with hemoglobin (correlation coefficient >0.9), it was not included as an explanatory variable in the multivariate analysis. *p < 0.05 (statistically significant variables). eGFR: estimated glomerular filtration rate; AST: aspartate aminotransferase; ALT: alanine aminotransferase; OR: odds ratio; CI: confidence interval.

Performance of Hemoglobin Levels as a Predictor of Persistent Hypotension

Using preoperative hemoglobin levels as the predictor in ROC curve analysis yielded a cutoff value of 12.9 g/dL for identifying patients at risk of persistent hypotension (sensitivity, 0.60; specificity, 0.67; positive predictive value, 0.27; negative predictive value, 0.90; area under the curve, 0.64) (95% CI, 0.52–0.75; p = 0.02) (Fig. 2). When patients were stratified based on this cutoff value, persistent hypotension occurred in 18 of 68 patients (26.5%) with hemoglobin levels ≤12.9 g/dL, compared to 12 of 115 patients (10.4%) with hemoglobin levels >12.9 g/dL, indicating a significantly higher incidence in the lower hemoglobin level group (p < 0.01).

Fig. 2. ROC Curve of Hemoglobin Levels for Predicting the Incidence of 5-ALA-Associated Persistent Hypotension

The area under the curve for ROC curve was 0.64 (95% CI, 0.52–0.75, p = 0.02). The cutoff value of hemoglobin levels for predicting the incidence of 5-ALA-associated persistent hypotension was 12.9 g/dL. 5-ALA: 5-aminolevulinic acid; ROC: receiver-operating characteristic.

DISCUSSION

As 5-ALA can induce severe hypotension, effective strategies for managing 5-ALA-associated hypotension are urgently needed. This study focused on persistent hypotension extending into the day following 5-ALA administration and aimed to identify associated clinical risk factors. Our findings demonstrated an independent association between lower preoperative hemoglobin levels and persistent hypotension.

A key strength of this study lies in its focus on persistent hypotension, which has been largely overlooked in previous studies. Given the pharmacokinetic profile of 5-ALA, which shows peak plasma concentrations of its metabolite PpIX within 4 h and a subsequent rapid decline,¹⁴⁾ most previous studies have concentrated on intraoperative hypotension. In our cohort, intraoperative hypotension occurred in 69.5% of the patients, which is consistent with previous reports.^8–10) Although most cases of 5-ALA-induced hypotension typically resolve during the perioperative period,⁹⁾ several case reports have described persistent hypotension lasting >24 h,¹⁶⁾ including severe cases complicated by transient bradycardic arrest.¹¹⁾ These findings highlight the importance of postoperative hemodynamic monitoring and the need for clinicians to be vigilant of persistent hypotension following 5-ALA administration. In our study, 16.4% of patients who experienced hypotension on the day of 5-ALA administration developed persistent hypotension on the day following surgery, indicating a clinically relevant incidence. To the best of our knowledge, this is the first study to specifically investigate persistent hypotension after 5-ALA administration.

The major finding of our study was that a lower preoperative hemoglobin level was associated with persistent hypotension induced by 5-ALA. The conversion of 5-ALA to heme requires iron incorporation into PpIX, catalyzed by FECH.¹⁾ Iron deficiency may impair this process and potentially delay PpIX metabolism. Experimental studies have shown that 5-ALA enhances nitric oxide (NO) production in human umbilical vein endothelial cells.²¹⁾ In turn, NO activates soluble guanylate cyclase, promoting vasodilation.²²⁾ These findings support the hypothesis that PpIX contributes to vasodilation via soluble guanylate cyclase activation.¹³⁾ Thus, in patients with low hemoglobin levels, which may reflect iron deficiency, delayed clearance of PpIX may contribute to prolonged vasodilation, resulting in persistent hypotension. A previous study reported a correlation between hematocrit levels and blood pressure variability from baseline following 5-ALA administration, including effects observed on the day after administration.¹⁶⁾ In the present analysis, hematocrit showed a strong correlation with hemoglobin and was significantly lower in the persistent hypotension group. These findings suggest that hematocrit may also serve as a predictor of persistent hypotension. However, hemoglobin is theoretically a more direct indicator of iron deficiency than hematocrit; therefore, preoperative hemoglobin may be a better predictor of persistent hypotension induced by 5-ALA. In contrast, previous reports on intraoperative hypotension following 5-ALA administration identified eGFR and the type of anesthesia as associated factors. In our study, most patients had relatively preserved renal function, which may explain the absence of an association between eGFR and persistent hypotension. Moreover, the pathophysiology of persistent hypotension may differ from that of intraoperative hypotension, which could explain why factors previously reported to be associated with intraoperative hypotension after 5-ALA administration were not identified in the present analysis. Our findings suggest a possible association between low hemoglobin levels and 5-ALA-induced persistent hypotension. However, the mechanism remains speculative because iron status, ferritin levels, and plasma PpIX concentrations were not measured in this study. Future investigations incorporating pharmacokinetic and mechanistic assessments are required to clarify this potential pathway.

Our study demonstrated the identification of a hemoglobin cutoff of 12.9 g/dL for predicting the incidence of persistent hypotension. Notably, this value is near the lower limit of the normal range, indicating that even “normal” hemoglobin levels may confer a risk. Persistent hypotension in the postoperative setting is associated with an increased risk of in-hospital falls.²³⁾ Furthermore, hypotension after noncardiac surgery has been reported to be associated with postoperative acute kidney injury,²⁴⁾ suggesting that sustained hypoperfusion due to persistent hypotension may contribute to organ dysfunction. Although persistent hypotension was generally mild in our cohort, a small number of patients experienced delayed intensive care unit discharge due to the need for continued hemodynamic monitoring (data not shown). This indicates that persistent hypotension may have clinical implications for postoperative resource utilization, even in the absence of overt organ dysfunction. Thus, the early identification and management of 5-ALA-induced persistent hypotension may help prevent adverse outcomes. Our findings offer preliminary insights that could inform perioperative risk assessments in patients receiving 5-ALA. Although hemoglobin demonstrated a statistically significant association with persistent hypotension, its discriminatory ability was modest. The cutoff of 12.9 g/dL yielded a low positive predictive value (27%) but a high negative predictive value (90%), indicating limited clinical utility as a standalone predictive marker. Therefore, hemoglobin should be interpreted as a component of risk assessment rather than a definitive predictor. Several previously reported risk factors for intraoperative hypotension following 5-ALA administration were not associated with persistent hypotension in the present study. Future large-scale studies are required to identify the additional contributing factors.

Our study had some limitations. First, the small number of patients with persistent hypotension limits the statistical power and may have led to a type II error. Therefore, further analyses with larger numbers of patients are required. Second, this study included only patients with bladder cancer. Given that 5-ALA is also used in patients with glioma,²¹⁾ hemodynamic responses to 5-ALA may differ depending on the cancer type; therefore, external validation in other patient groups is required. Third, due to the retrospective nature of the study, data on postoperative fluid management and clinical outcomes related to persistent hypotension, PpIX levels, and iron or ferritin status were not available, which limited further mechanistic interpretation. In particular, the exact timing of 5-ALA administration relative to anesthesia induction and postoperative fluid balance may influence postoperative hypotension, and future prospective studies incorporating these data are warranted to validate the present findings. Fourth, anesthesia, hemodynamic management, and the preoperative discontinuation of antihypertensive medications, as well as postoperative management, were determined at the discretion of individual anesthesiologists and attending physicians, respectively. Additionally, we could not assess the duration of hypotension, as only the initial postoperative SBP value was available for all patients. These may have introduced variability in blood pressure control strategies. Finally, a history of preoperative hypotension was not used as an exclusion criterion in this analysis. However, because baseline blood pressure was included as an explanatory variable in the multivariate analysis, the influence of preoperative hypotension history on the present results is considered minimal. Despite these limitations, and given the limited evidence of persistent hypotension associated with 5-ALA, this study provides important insights into blood pressure management in relation to 5-ALA administration.

In conclusion, we identified low preoperative hemoglobin levels as a risk factor for persistent hypotension following 5-ALA administration. Although further validation is required, clinicians should be aware of the potential risk of persistent hypotension and consider extended hemodynamic monitoring in patients receiving 5-ALA.

DECLARATIONS

Conflict of Interest

The authors declare no conflict of interest.

Use of Generative AI

We used ChatGPT, a large language model developed by OpenAI, to assist with English editing during manuscript preparation. The authors reviewed and revised the AI-generated text to ensure accuracy and appropriateness, and they take full responsibility for the final content of the manuscript.

Data Availability

The anonymized data of this study are available on request from the corresponding author.

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