Trigger Unhappy? New Evidence Supports Mental Stress Can Trigger Microvascular Occlusion and Potentially Lead to Sickle Cell Pain Crisis

Individuals living with sickle cell disease (SCD), as well as their providers, often try to identify specific triggers that result in acute vaso-occlusive pain episodes (VOEs). I commonly ask my patients, “What do you think triggered this ‘crisis?’” A robust review of systems includes questions such as, “Do you know your triggers? What typically causes you to go into a pain crisis? Have you been able to do anything to prevent a crisis?” The aim is to help the individual identify and isolate common inciting events of VOEs, implement strategies to mitigate these triggers and reduce the frequency of acute exacerbations, and ultimately improve their quality of life. Several publications have cited hypoxia, infection, changes in weather, dehydration, emotional stress, and overexertion as common triggers of sickle cell crises.^1-4  However, until now, there has not been an objective assessment of the physiological relationship between mental stress and acute vasoconstriction in SCD, though anecdotally many of us believe and practice as though stress were a clearly defined exacerbator of the sickle state.

Psychological stress has been temporally associated with pain and health care use in adolescents and adults with SCD,^5,6  and this is believed to be mediated by autonomic nervous system (ANS) pathways. Individuals with SCD are believed to have attenuated autonomic nervous system–mediated vasoconstriction in response to stressful stimuli including pain, hypoxia, and sighing.⁷  In an elegant study by Dr. Maha Khaleel and colleagues,⁷  investigators demonstrated that individuals with SCD had an exaggerated vasoconstriction response to the anticipation and direct application of painful heat stimuli to one arm, with a decreased microvascular perfusion in both arms. While subjective measures of pain threshold and pain tolerance were similar between SCD and controls, there was a significantly higher vasoreactivity index in the microvascular flow response to thermal pain in SCD (p=0.0028). They postulated that this exaggerated global vasoconstriction response in SCD increases red cell transit time through circulation and increases propensity for vaso-occlusion.

Taking this a step further, Dr. Payal Shah and colleagues sought to investigate the objective impact of mental stress on vasoconstriction parameters in patients with SCD versus controls. Under strictly controlled settings they evaluated 20 patients with SCD and 16 controls, with similar baseline characteristics (except for hemoglobin on testing day) who underwent a standardized psychological stress induction protocol. This involved randomly assigning patients to do a memory task test (N-back) or a conflict task (Stroop) followed by a pain anticipation test (PA) with a measure of state anxiety between tasks. During the PA test, no actual pain stimulus was applied; however, subjects were asked to read on their computer screen the following sentence: “You will receive a maximum pain stimulus in one minute. When you cannot tolerate the pain any longer, say STOP and the device will cool down to normal level immediately.”

Results showed a significant drop in regional microvascular blood flow during experimentally induced mental stress (cognitive tasks and PA tasks). Pain anticipation yielded a greater drop in microvascular blood flow from baseline. No differences were detected in the magnitude of response between individuals with SCD and controls. Once vasoconstriction occurred, it remained throughout the whole task regardless of task difficulty. The degree of vasoconstriction was also found to be proportional to the magnitude of the stress. State anxiety had a higher effect on blood flow response in SCD patients versus controls (p=0.03) and having higher anxiety at baseline in SCD was associated with less change in blood flow in response to pain anticipation (p=0.002). Investigators found that highly anxious patients with SCD tended to have lower mean baseline blood flow and were therefore already vasoconstricted at baseline. Autonomic reactivity (parasympathetic withdrawal as well as sympathetic activation) was also noted in all subjects.