In the present study, we showed that administration of nimodipine during and after surgery can effectively prevent the occurrence of delayed CVS and improves the prognosis of CVS. After resecting the tumor, diluted nimodipine (stock solution: normal saline=1:5) was soaked into the surgical field for 10 minutes, and then nimodipine was continuously infused via a micropump. For patients weighing less than 70 kg or having unstable blood pressure, the starting dose was 0.5 mg/h, and if the patient tolerated this dose well, the dose was increased to 1 mg/h after 2h. For patients weighing more than 70 kg, the starting dose was 1 mg/h, and if the patients tolerated this dose well, the dose was increased to 2 mg/h after 2h and administered for 14 days. Thereafter, nimodipine was administered orally (60 mg, once a day, for 7 days). CVS after intracranial tumor craniotomy is a multifactorial clinical syndrome. CVS is caused by an extreme contraction of the arteries and tense vascular smooth muscle. The mechanisms underlying CVS remain unclear; it may be multifactorial and involve a complicated pathological process. Potential causes of CVS are as follows: 1. mechanical stimulation such as damage, compression or stretching of the blood vessels during surgery, leading to the blood flowing into the subarachnoid space and subsequent occurrence of CVS occurs; 2. vascular wall injury caused by compression of the vascular wall and vascular wall malnutrition; 3. damage caused by the oxidation of hemoglobin to methemoglobin and release of oxygen free radicals; 4. constriction of the blood vessels caused by vasoactive substances; 5. increased intracranial pressure, the overdose of dehydration drugs and insufficient supply of blood volume; and 6. inflammation and immune reactions of blood vessel walls[6, 22, 23]. The common final pathway arising from all the above factors stated is a change in the permeability of smooth muscle cells in the blood vessels, an increase in calcium influx and release of calcium ion from intracellular calcium stores, leading to an overload of free calcium in the cytosol. When a critical constriction concentration is reached following the opening of calcium channels, extracellular calcium enters the cells and is released from the calcium stores, leading to an increase in the concentration of free calcium in the cytosol; thus, vasospasm occurs. Therefore, calcium overload is believed to be the most important phenomenon during the generation of vasospasm.
There are two types of calcium channels, voltage-dependent and receptor-operated. The former is located in the cell membrane of heterologous multimeric transmembrane proteins. These channels are activated at depolarized membrane potentials and are the source of the "voltage-dependent" epithet. The concentration of calcium (Ca2+ ions) is normally several thousand times higher outside of the cell than inside. Activation of particular VDCCs allows Ca2+ to rush into the cell, which depending on the cell type, results in activation of calcium-sensitive potassium channels, muscular contraction, excitation of neurons, upregulation of gene expression, or release of hormones or neurotransmitters. The opening of this type of channel is related to voltage and occurs due to the depolarization of the smooth muscle cell membrane after the channel is activated and excited. The opening of the latter channel is caused by the stimulation of receptors of the cell membrane by certain substances, such as 5-hydroxytryptamine and adrenalin. Subsequently, calcium influx increases, and calcium release occurs, leading to vasospasm caused by the abovementioned mechanism. These findings provide evidence for the potential prevention of CVS using calcium channel blockers.
It has been shown that nimodipine significantly reduced symptoms caused by secondary ischemia after SAH; consequently, the risks of death and paralysis caused by CVS were markedly reduced. Currently, nimodipine is considered as the first choice for the prevention of CVS after SAH. Nimodipine is a second-generation dihydrotestosterone pyridine class calcium antagonist with the highest lipid solubility. High lipophilicity of nimodipine facilitates its movement through the blood-brain-barrier, and nimodipine is also highly selective for vascular smooth muscle due to the dihydrotestosterone pyridine ring. Moreover, nimodipine can block L-type voltage-dependent calcium channels in the cell membrane of vascular smooth muscles, effectively inhibiting calcium influx and simultaneously activating Ca2+-ATP, which promotes depletion of cytoplasmic calcium and enhances calcium intake and storage from the mitochondria and endoplasmic reticulum, thereby regulating the concentration of intracellular Ca2+ and maintaining normal physiological functions. Moreover, nimodipine can inhibit aggregation of platelets and leukocytes, reducing erythrocyte rigidity and blood viscosity and preventing the release of 5-HT and arachidonic acid and other vasoactive substances that cause vasoconstriction.
In addition, nimodipine can significantly improve cerebral blood circulation after brain injury, preventing secondary brain damage and promoting brain function recovery. Nimodipine lavage can effectively improve the prognosis of secondary cerebral vasospasm after SAH[33-35]. Our findings revealed that infusion and oral intake of nimodipine after nimodipine lavage during surgery are effective in the prevention of the development of delayed CVS after intracranial tumor craniotomy. The incidence of CVS in the nimodipine group (25%) was significantly lower than that in the normal saline group (45%). In addition, the MCA velocity was significantly lower in the nimodipine group than in the normal saline group after surgery. Prognoses appeared to be remarkably improved in the nimodipine group.
To date, regarding the diagnosis of CVS after intracranial tumor craniotomy, digital subtraction angiography (DSA) and TDU are believed to be effective CVS detection methods. DSA had been a gold standard for the diagnosis of CVS. However, if the blood vessel is too small to be detected by DSA, misdiagnosis of CVS might occur. Because DSA is an invasive examination and could produce risks such as iatrogenic stroke and rupture of the blood vessels, the application of DSA is limited for the detection of CVS[26, 38]. Additionally, TDU has the advantage of being economical, non-invasive, real-time, and repeatable, offering continuous monitoring with high sensitivity and specificity; thus, TDU has become the first-line procedure in the detection of CVS. Blood flow velocity (VBF) is determined by cerebral blood flow (Q) and the diameter of cerebral blood vessels (D). The formula is as follows: VBF=4 Q/D2, with the velocity being inversely proportional to the diameter when blood volume does not change. Smaller blood vessels have faster blood flow velocity; therefore, hemodynamic changes, such as high velocity and high resistance, can occur. Thus, the extent of blood vessel narrowing can be estimated by the alteration of blood flow velocity. Moreover, the MCA is the best blood vessel for monitoring CVS[41, 42]. The human MCA is a terminal branch of the ICA, has few collateral branches and has a long and straight stem. The MCA is easily detected, has high specificity, and its diameter is negatively correlated with the blood flow velocity and is positively correlated with vasospasms. Based on these facts, the MCA is typically examined to detect CVS.
In this study, blood flow velocity prior to CVS was measured as baseline velocity and was compared with that after surgery at different time points. Furthermore, comparing changes in blood flow velocity in the MCA allows the objective detection of CVS. However, different operators of TDU might obtain different results due to unavoidable subjective factors such as the variable angle of the ultrasound probe that was used. In this study, the same doctor performed TDU examinations in all patients, which made the examination data reliable. Our results showed that TDU can be effectively used for the diagnosis of CVS after intracranial tumor surgery. If the flow velocity in the MCA is more than 120 cm/s, and Lindegaard index is more than 3, a diagnosis of CVS is confirmed.
We showed that the application of nimodipine during and after surgery can effectively prevent the occurrence of delayed CVS and improve the prognosis of CVS. Notably, the retrospective cases in our study were limited. If larger sample sizes are available, general problems can be studied more clearly.