The clinical courses of the two patients suggest some important findings following 5-ALA pretreatment: first, severe postural hypotension followed 5-ALA pretreatment; second, severe postural hypotension occurred about 3 h after 5-ALA pretreatment; and third, the hypotension was severe in the abrupt onset and duration.
The clinical situations of the two patients may indicate a causal relationship between severe postural hypotension and exposure to 5-ALA, this being the common clinical factor between them. The possible causes of the postural hypotension observed in the two patients could be strong vasodilation and autonomic disorder. 5-ALA may induce vasodilative action ; however, it is debatable whether severe hypotension is ascribed only to vasodilative action because 5-ALA does not always induce severe BP decrease and its dose-response relationship is unclear. According to previous researches, there have been some concerns about the relationship between 5-ALA-induced hypotension and antihypertensive therapy [6, 7]. Although preanesthetic antihypertensive may be a factor spurring hypotension, it is uncertain whether the severe postural hypotension was only due to 5-ALA pretreatment in combination with the antihypertensive because 5-ALA-pretreated patients medicated together with antihypertensive have not always experienced preanesthetic severe hypotension in clinical practice. Previous trials contain no information on how patients moved to the operation room. In neurosurgical trials, patients with high-grade glioma are considered to have been laid on the bed before an operation. Postural hypotension may not have developed in neurosurgical trials because such patients hardly have the need to walk to the operation room and are usually transferred on the bed. While we have hypothesized that autonomic reflex dysfunction or strong vasodilation beyond autonomic reflex may be responsible for the severe hypotension observed in our patients, the true mechanism is not known.
The onset time of severe hypotension in our cases was approximately 3 h after 5-ALA pretreatment, similar to a recent report  and seems to coincide with an increase in plasma PpIX concentration. PpIX concentration slopes upward an hour after 5-ALA pretreatment, and the 3-h concentration reaches about 3 times as high in an hour , indicating that substantial exogenous 5-ALA yields high concentrations of porphyrin precursors, similar to porphyria in terms of high porphyrins. While it was concluded that 5-ALA does not induce porphyria [8, 9], there is a report presenting a patient with 5-ALA-induced acute neuropathy similar to porphyria who experienced recurrent postural hypotension . Postural hypotension is among the signs of porphyria autonomic neuropathy, and ample 5-ALA is supposed to have direct neurotoxicity [11,12,13]. Considering this fact, it is possible that autonomic dysfunction develops around 3 h after 5-ALA pretreatment when the concentration of porphyrin precursors becomes extremely high. Given that substantial exogenous 5-ALA can neurogenically affect BP regulation, consultation from a neurologist may be needed.
The abrupt onset of profound hypotension and duration of BP decrease was serious; therefore, anaphylactic shock should be differentiated. 5-ALA can induce hypersensitivity. Two previous clinical studies have each listed a case with 5-ALA-related rash  and urticaria , and anaphylactic shock occurred in a patient with intravesical 5-ALA-derivative . Thorough inspections for hypersensitivity may be required in severe cases . According to a recent report, 5-ALA-induced hypotension may possibly be vasoactive-refractory . While severe hypotension improved in the first case, the second case suffered prolonged hypotension that continued by the next day despite continuous dopamine infusion. Although it is not fully elucidated what classes of antihypertensive drugs significantly contribute to 5-ALA-induced hypotension, preoperative administration of angiotensin-receptor-blocker is known to be associated with an increased incidence of intraoperative hypotension [15, 16]. Losartan was administered in the second case, taking into account its advantages and disadvantages, but it may have been attributed to the severity and prolonged duration of 5-ALA-induced hypotension. Given that the effects of 5-ALA are strong and long-lasting, adequate vasoactives and careful monitoring over a day will be necessary when dealing with 5-ALA-induced hypotension.
When treating patients with 5-ALA pretreatment, there are some important insights elicited from the present cases. Standing should be avoided, and it is beneficial not to take vasodilatives preoperatively together with 5-ALA. Checking for vital signs is needed around 3 h after 5-ALA pretreatment. Preparation for prolonged hypotension may be required. As for 5-ALA indication, it is necessary to elucidate whether a history of 5-ALA-induced hypotension is a risk factor for the next 5-ALA pretreatment, because a previous study described recurrent symptomatic hypotension in patients with similar hypotensive histories . However, the description lacks sufficient clinical details to draw generalizations.
In conclusion, we admitted two patients with severe postural hypotension following 5-ALA pretreatment. One patient managed to undergo PDD TURBT with general anesthesia after recovering from the hypotension, but the other could not undergo the procedure due to prolonged hypotension. Since 5-ALA may affect the nervous system, the severe hypotension observed in our patients may be attributable to the effects of 5-ALA-induced autonomic dysfunction. As such, careful monitoring of the vital signs during perioperative period is required after 5-ALA pretreatment and patients so treated should avoid standing. The relationship between 5-ALA and porphyrin metabolism may be investigated to unravel possible mechanisms for severe hypotension.