Subclinical Hyperprolactinemia Induced by Calcium Channel Blockers in ICU Patients: Clinical Relevance or Epiphenomenon?1-Abstract : Background:Hyperprolactinemia is a frequent biochemical finding in critically ill patients and is often attributed to stress, altered dopaminergic tone, or pharmacologic agents. Calcium channel blockers (CCBs), particularly non-dihydropyridine agents, have been sporadically associated with elevated prolactin levels; however, the clinical relevance of this association in intensive care unit (ICU) patients remains unclear. Objective:To evaluate the effect of calcium channel blocker administration on serum prolactin levels in ICU patients and to determine whether observed elevations represent a clinically meaningful phenomenon or an epiphenomenon related to critical illness. Methods:A prospective observational before–after study was conducted in adult ICU patients receiving intravenous or oral CCBs. Serum prolactin levels were measured prior to CCB initiation and 72 hours after treatment. Demographic data, illness severity, CCB type and dose, and potential confounders were recorded. Statistical analysis included paired t-tests and subgroup comparisons. Results:Eighty-four patients were included. Mean prolactin levels increased significantly after CCB administration (baseline: 18.6 ± 6.4 ng/mL vs. post-CCB: 29.8 ± 9.1 ng/mL, p < 0.001). The increase was more pronounced with non-dihydropyridine CCBs and higher cumulative doses. No patient developed clinical manifestations attributable to hyperprolactinemia. Conclusions:CCB therapy in ICU patients is associated with a mild but statistically significant increase in prolactin levels. In the absence of clinical symptoms, this elevation appears more consistent with an epiphenomenon than a clinically actionable endocrine disorder.2-Introduction Hyperprolactinemia refers to an abnormal elevation of serum prolactin, a pituitary hormone regulated predominantly by tonic dopaminergic inhibition. While overt hyperprolactinemia is classically associated with reproductive and metabolic disturbances, mild or subclinical elevations are frequently observed in hospitalized and critically ill patients. Calcium channel blockers (CCBs) are commonly used in the ICU for the management of hypertension, arrhythmias, and ischemic heart disease. Experimental and clinical evidence suggests that calcium influx plays a role in hypothalamic and pituitary hormone secretion. Interference with calcium-dependent signaling pathways by CCBs may therefore alter prolactin release. Critically ill patients represent a unique population in whom neuroendocrine regulation is profoundly altered by stress, inflammation, and polypharmacy. Distinguishing drug-induced hormonal changes from illness-related adaptations remains challenging. The present study addresses this gap by systematically examining prolactin changes associated with CCB use in ICU patients and evaluating their potential clinical relevance. 3-Objectives of the Study 1. To quantify changes in serum prolactin levels before and after initiation of calcium channel blockers in ICU patients. 2. To compare prolactin responses across different CCB classes and doses. 3. To assess whether subclinical hyperprolactinemia observed in this context has clinical significance. 4- Literature Review Early experimental studies in the late 1970s demonstrated that calcium flux is essential for pituitary hormone secretion. During the 1980s, isolated clinical observations reported elevated prolactin levels in patients treated with verapamil. Subsequent small clinical trials in the 1990s confirmed transient prolactin elevations following intravenous administration of non-dihydropyridine CCBs. In the early 2000s, attention shifted toward drug-induced endocrine disturbances in hospitalized patients. Several reviews noted CCBs as uncommon but plausible contributors to hyperprolactinemia. More recent literature has emphasized the high prevalence of hormonal abnormalities in ICU patients, often without clear clinical consequences. Despite these observations, robust data focusing specifically on critically ill populations remain scarce. Most available studies are limited by small sample sizes, heterogeneous populations, and lack of standardized timing for hormone measurements.5-Methods Study Design Prospective observational before–after study conducted in a mixed medical-surgical ICU. Participants Adult patients (≥18 years) requiring CCB therapy for at least 72 hours. Exclusion Criteria: • Known pituitary disease • Pregnancy or lactation • Dopamine antagonist therapy • End-stage renal disease Data Collection • Serum prolactin measured at baseline and 72 hours post-CCB initiation • CCB type and cumulative dose recorded • Severity of illness assessed using APACHE II score Statistical Analysis Data are presented as mean ± SD. Paired t-tests were used for before–after comparisons. Subgroup analyses were performed using ANOVA. A p-value <0.05 was considered statistically significant.6- Results The distribution of patients according to the class of calcium channel blockers (CCBs) administered during ICU admission. A total of 84 patients were included in the analysis.Dihydropyridine calcium channel blockers, including amlodipine and nifedipine, were prescribed to 46 patients, accounting for 54.8% of the study population. In contrast, non-dihydropyridine calcium channel blockers, such as verapamil and diltiazem, were administered to 38 patients, representing 45.2% of cases. Overall, the data demonstrate a relatively balanced use of both CCB classes in the ICU setting, with a slight predominance of dihydropyridine agents. The distribution of patients according to serum prolactin status after calcium channel blocker therapy, based on predefined biochemical criteria. A total of 84 patients were evaluated.Normal prolactin levels (≤25 ng/mL) were observed in 49 patients, representing 58.3% of the study population. Subclinical hyperprolactinemia, defined as prolactin levels between 26 and 50 ng/mL, was identified in 31 patients (36.9%).Only 4 patients (4.8%) developed overt hyperprolactinemia, with prolactin concentrations exceeding 50 ng/mL. Importantly, these cases were not associated with clinically significant symptoms.Overall, the findings indicate that while biochemical elevations in prolactin were relatively common following calcium channel blocker exposure, the majority of cases remained within the normal or subclinical range. Comparing the mean increase in serum prolactin levels according to the class of calcium channel blockers (CCBs) administered to ICU patients.Patients treated with dihydropyridine calcium channel blockers demonstrated a mean prolactin increase of 7.2 ng/mL, with a standard deviation of ±3.1 ng/mL. This increase was statistically significant (p < 0.01).In contrast, patients receiving non-dihydropyridine calcium channel blockers exhibited a substantially greater rise in prolactin levels, with a mean increase of 14.1 ng/mL and a standard deviation of ±5.6 ng/mL. This association showed a stronger statistical significance (p < 0.001).Overall, the findings indicate that non-dihydropyridine calcium channel blockers are associated with a more pronounced elevation in prolactin levels compared to dihydropyridine agents, despite both drug classes demonstrating statistically significant effects. 7-Discussion The present study demonstrates a statistically significant increase in serum prolactin levels following CCB administration in ICU patients. The magnitude of elevation was modest and more pronounced with non-dihydropyridine agents, consistent with prior experimental data. Importantly, no patient exhibited clinical manifestations of hyperprolactinemia. This finding supports the interpretation that the observed biochemical changes are likely an epiphenomenon reflecting altered neuroendocrine regulation in critical illness rather than a clinically relevant adverse drug effect. These results align with previous reports suggesting that mild hormonal abnormalities in ICU settings often lack independent prognostic or therapeutic implications. Nevertheless, awareness of this association may help avoid unnecessary diagnostic evaluations. 8-Conclusion Calcium channel blocker therapy in critically ill patients is associated with mild, subclinical elevations in prolactin levels. In the absence of symptoms, these changes appear to represent an epiphenomenon rather than a clinically significant endocrine disorder. Future studies with larger cohorts and longer follow-up are warranted to confirm these findings.
Omar et al. (Sun,) studied this question.