In the present study, we applied multivariate logistic regression analysis combined with PSM to investigate the relationship between sPi levels and aHCP. The significant findings of this study were as follows: 1) A lower admission sPi level was considered as a risk factor of aHCP; 2) mFisher scale and Hunt-Hess grade were negatively correlated with sPi, respectively; 3) Patients with severe aSAH (higher mFisher score and Hunt-Hess grade) have significantly lower sPi levels; 4) The sPi level was negatively associated with SBP;5) The model constructed by sPi levels, Hunt-Hess grade, and mFisher scale significantly improves the prediction of aHCP after aSAH. Risk factors for aHCP have been reported, including mFisher score, Hunt-Hess grade in aSAH patients, which were balanced in this study. After PSM, no significant differences were observed in the mFisher score, Hunt-Hess grade between the two groups. The matched aHCP group had a lower sPi level compared with the matched non-bleeding group in the univariate analysis. The sPi level was considered as a risk factor of aHCP, which was confirmed after PSM analysis. The AUC of the combined model was 0.840 with a sensitivity of 88.6% and specificity of 68.4% for aHCP. The model constructed by sPi levels, Hunt-Hess grade, and mFisher scale produced the best ability to predict aHCP compared with a single sPi level or mFisher scale, which was a valuable factor for predicting the occurrence of aHCP following aSAH. Previously reported literature demonstrated that aHCP and diffuse cerebral edema are more common in patients with non-traumatic intracranial hemorrhage accompanied by decreased sPi levels[17]. Based on it, we listed aSAH from non-traumatic ICH to explore the relationship between decrease sPi levels and aHCP. The present study consolidated and expanded previous observations[17] and constructed an unexpected and novel combined model for predicting aHCP.
Phosphate metabolism is an evolving field of basic and clinical research. Phosphorus is essential for all living cells, accounting for about 1% of human body weight. The most phosphate (85%) is found in bones and teeth, and the remaining 15% is distributed in body fluids and other cells[15, 16]. Phosphate as an energy source in the form of ATP is essential for cell metabolism and the normal development of bones. Phosphate is an essential mineral that participates in many physiological pathways and mineralization, the essential elements of membrane composition, such as the formation of various enzymes, the components of DNA and RNA, cell signaling, energy storage, transfer, and maintenance of acid-base equilibrium[16, 20, 22].
Decreased sPi concentration is a common phenomenon after non-traumatic ICH, including aSAH[17, 22], which may be caused by increased renal excretion, decreased intestinal absorption, or internal redistribution of inorganic phosphate[16, 22]. The redistribution of inorganic phosphate across cell membranes is the most common cause of hypophosphatemia in patients and can be caused by various clinical conditions[26]. The underlying mechanism is attributed to the following reasons. Firstly, spontaneous hyperventilation is very common in patients with aSAH[27]. In respiratory alkalosis, a decrease in carbon dioxide can trigger an increase in intracellular pH, which stimulates phosphofructokinase, leading to increased glycolysis and the incorporation of phosphate into organic intermediates[28, 29]. Therefore, this causes a decrease in phosphate in the cell, which transfers phosphate into the cell. Some reports in the literature have revealed that during hyperventilation, the patient’s serum phosphate level is as low as 0.3 mmol/L[27], which may be the most common cause of hypophosphatemia in hospitalized patients. Reduced sPi concentration caused by respiratory alkalosis is also seen in patients with head injuries, acute strokes, and mechanical ventilation[28, 30]. Secondly, high serum levels of endogenous or exogenous catecholamines (such as epinephrine and norepinephrine) in patients after aSAH can lead to a decrease in serum phosphate[31]. Reported literature hinted sPi is inversely related to the paroxysmal sympathetic storm and increased plasma epinephrine[32]. Adrenaline can raise blood pressure, and our data also indicated that patients with lower sPi levels had higher SBP than those with higher sPi levels. Our findings are consistent with the literature in implying a negative correlation between the initial sPi concentration and plasma epinephrine[31, 33]. Thirdly, serum phosphate levels are negatively correlated with the levels of inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α)[10, 34]. Elevated inflammatory factors lead to internal redistribution of phosphorus, and decreased serum phosphate may be due to increased use of phosphate by immune cells.
aHCP is not an uncommon complication and is a potentially treatable cause of early neurological deterioration following aSAH. Systemic inflammatory response syndrome is common in aSAH[12, 35]. aHCP is characterized by enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles from failed CSF homeostasis. Since the 1840’s, inflammation in the brain and the CSF spaces have been detected in both post-hemorrhagic and post-infectious hydrocephalus[36]. Inflammatory cells might be an independent predictive factor associated with aHCP after aSAH. Recent studies have begun to reveal the molecular mechanisms by which inflammation-regulating cytokines, immune cells, and signaling pathways- contribute to the pathogenesis of hydrocephalus[10, 36]. The cytokines, immune cells, and signal pathways all require the participation of phosphate. aSAH can accelerate cell apoptosis. Phosphate is released from dead cells into blood vessels, promotes vascular inflammation and endothelial cell apoptosis[36]. In the present study, a reduction of serum phosphate was observed in patients with aHCP following aSAH, supporting a possible link between phosphate metabolism, inflammation, and hydrocephalus.
Numerous mechanisms have been implicated as causative factors for the development of aHCP following aSAH, including obstruction of the arachnoid granulations by blood products, alterations in CSF dynamics, and adhesions within the ventricular system[6, 10]. Emerging data have established that inflammatory pathways are likely to play an essential role in the pathogenesis of aHCP. Inflammatory markers in CSF and peripheral blood are associated with the possibility of developing aHCP[9, 10, 12, 36]. Lower sPi levels are negatively correlated with the levels of inflammatory cytokines[16]. This study determined that a lower admission sPi level is considered a risk factor for aHCP. It seems consistent with previous literature that Inflammation can induce aHCP[36].
Impaired early energy metabolism in the brain may be another mechanism that causes aHCP after aSAH. In this study, we observed decreased serum phosphate was associated with higher severity of aSAH, consistent with existing literature [17]. Phosphate is the most abundant intracellular anion and is involved in synthesizing various enzymes in the body. It is necessary to produce ATP and 2,3-diphosphoglycerate in red blood cells, which helps to release oxygen from hemoglobin[37]. Therefore, a decreased sPi level is likely to shift the hemoglobin dissociation curve to the right and increase the affinity of hemoglobin for oxygen, resulting in a decrease in oxygen release, thereby impairing brain energy metabolism, aggravating brain damage, and affecting the virtuous circulation of CSF[38]. The above process may lead to subsequent aHCP. In addition, lower sPi levels may aggravate the destruction of the blood-brain barrier and further aggravate the occurrence of aHCP.
The influence of sPi levels on the prognosis of critically ill patients, including aSAH, is controversial[17, 22]. Our current data demonstrated that lower sPi levels at admission were observed in patients with unfavorable outcomes. However, according to the ROC curve, the AUC of sPi is 0.602 for mRS, indicating that the predictive value of sPi in predicting poor prognosis is weak. The presence of a lower sPi level may be just another indicator of disease severity, not a major contributor factor to disease severity. This hypothesis is supported by our findings that there is a negative correlation between the initial phosphate concentration and the commonly used disease severity scores, including mFisher score and Hunt-Hess grade. This association has been observed in some previous studies, but the opposite results have also been reported[17]. Of course, their research objects are not patients with sICH. Therefore, it seems reasonable that the conclusions are different.
Limitation
Limitations of this study include sample size and observational single-center study, which may limit the generality of our results. Furthermore, all laboratory data are initial values at admission, and increased dynamic analysis of follow-up data may help improve our findings. Thirdly, factors affecting serum phosphorus have not been considered, including eating habits, food intake, and hormone levels. Finally, related inflammatory cytokines, such as C reactive protein, procalcitonin, and IL-6, were not included in the analysis