Intoxication caused by ASA and its derivatives is a frequent occurrence in all ages. Because there is no antidote for salicylate poisoning, treatment relies on prompt clinical evaluation, avoiding additional intestinal absorption of the drug, preventing its entry into the central nervous system (CNS), improving its clearance from the CNS, and hastening its elimination from the body [22].

In this study, the authors compared the influence of different fluid types isotonic saline NaCl (0.9%), RL, and albumin, administered alone or as a combination in an experimental model of acute salicylate toxicity in rats. The current results revealed significant acute salicylate toxicity in the ASA-administered group after 2 doses of ASA on two successive days. The rat’s toxic signs were assessed by measuring pulmonary function tests using a spirometer which denoted a marked respiratory distress and a significant. Drop in the respiratory rate compared to the normal control group. ABG parameters revealed significant acidosis, hypoxemia, and hypercapnia accompanied by consuming the alkaline component HCO3 and significant hypokalemia compared with that in the control groups. Also, the ASA-administered group showed a significant deterioration in liver function tests such as AST and ALT, and renal function tests such as BUN, and serum Cr. The GFR also revealed a marked reduction compared to the control group. The liver and renal derangement was confirmed by histopathology which showed hepatocytes hemorrhage, vacuolated cells with apoptotic-like bodies, disturbed bile duct, and fibroblasts. The renal sections showed degenerated shrunken glomeruli and a widening of Bowman’s capsule.

The results of the treated groups revealed marked variations in the animal’s response according to the fluid type, NaCl saline-treated group and RL-treated group; both showed a significant improvement in respiratory rate, ABG parameters, liver and kidney function tests, and histopathology which revealed preserved hepatic and renal structure. The results of the albumin-treated group and the combined isotonic saline and albumin group showed a variation from mild to no improvement in all previous parameters. The most interesting finding of this study is that the group that received a combination of RL and albumins showed the worst results regarding all investigated parameters compared to the control group and all other treated groups.

The most common consequence of acute ASA toxicity is acidosis which is the most common acid–base disruption. Salicylates affect cellular respiration by uncoupling oxidative phosphorylation. They stimulate medullary respiratory centers, resulting in primary respiratory alkalosis, which is frequently overlooked. Salicylates concurrently and independently generate primary metabolic acidosis. As salicylates leave the circulation, enter cells, and harm mitochondria, metabolic acidosis emerges as the major acid–base imbalance and results in hemodynamic instability, and end-organ failure [23]. Additional consequences of ASA poisoning involve the depletion of glycogen reserves and the impairment of gluconeogenesis, leading to a catabolic state that can cause hypoglycemia. Moreover, ASA leads to the accumulation of organic acids and keto acids. Finally, salicylate acts as an inhibitor of cyclooxygenase contributing to platelet dysfunction and injury to the gastric mucosa [24]. The cornerstones of therapy include good supportive care and prompt elimination of the toxin that was ingested. It is also crucial to promptly address complex metabolic imbalances, particularly acidosis and hypoglycemia, and rapid intravascular volume repletion. The presence of multiple issues and the involvement of unknown factors in salicylate poisoning can give rise to unpredictable and potentially fatal complications. Consequently, determining the most effective treatment method becomes exceptionally challenging [25].

In the current study, when we achieved rapid initial IV fluids administration, the isotonic saline NaCl 0.9%-treated group and the RL-treated group exhibited considerable improvement in all parameters, which was expected and can be related to the correction of dehydration and repletion of extracellular volume. Sing et al. 2023 explained that solution is a type of fluid used in volume resuscitation in which the intravascular volume expands, boosting preload and consequently perfusion. This solution is an isotonic crystalloid fluid that can also be classified as balanced or buffered. It contains numerous important components, such as sodium, chloride, potassium, calcium, and sodium lactate. These components are combined into a solution with an osmolarity of 273 mOsm/L and a pH of around 6.5 to correct volume depletion. Sing et al. emphasized that RL solution is particularly effective for vigorous fluid replacement in a variety of clinical settings while minimizing cellular death [26]. Growing evidence suggests that lactate is a preferred energy source that can be easily oxidized during times of energy crisis. The use of sodium lactate in RL provides the body with a bioenergetic fuel that the human body is naturally designed to metabolize when experiencing ischemic conditions. This metabolic process helps reduce cell death caused by tissue, ischemia which is consistent with our results [27].

Because salicylate is partially and reversibly bound to albumin protein, the unbound nonionized salicylate diffuses from plasma into organs and in higher doses causing tissue toxicity [24].

So, theoretically, the therapy of salicylate poisoning aims to keep salicylate concentrations from reaching deadly levels. Based on this information, the authors sought to determine if increasing albumin binding to salicylate in the blood via IV albumin infusion could reduce free salicylate levels. This method may induce salicylate to be redistributed from the tissues back into the plasma, potentially giving enough time for hemodialysis to begin in severe situations. However, the current results were not encouraging; the albumin-administered group and the combined isotonic saline NaCl (0.9%) and albumin group showed mild improvement in all investigational parameters despite the various beneficial effects of albumin. According to a study conducted by Curry and colleagues in 2007, using pigs as a model for acute salicylate poisoning, they discovered that administering an intravenous infusion of albumin at about 2.2 times the amount present in the bloodstream over 15 min resulted in a slight increase in both the total salicylate level in the blood and the fraction of salicylate bound to albumin proteins. However, this rise did not achieve statistical significance compared to the group that did not receive albumin.

In the same study a two-hour delay, it was shown that animals treated with albumin had a 14% decrease in salicylate levels in their brain which matched our results that didn’t show marked improvement in the albumin-treated group [14]. Furthermore, Ashton and colleagues conducted a human study in 1989 involving children, which elucidated that Kwashiorkor children with hypoalbuminemia had a four-fold increase in the free fraction of salicylic acid compared to normal children. This was attributed to the fact that some Kwashiorkor children exhibited significantly low concentrations of serum albumin, resulting in higher proportions of free salicylic acid in the bloodstream relative to the total salicylic acid concentration [28]. In addition, evidence indicates that albumin has various effects apart from its ability to maintain oncotic pressure. These effects include anti-inflammatory and antioxidant properties, safeguarding the glycocalyx, enhancing the integrity of endothelial cells, preventing endothelial cell death, and facilitating the binding of drugs and other substances in the plasma. Additionally, albumin exhibits a role in regulating acid–base balance, controlling shifts in electrolyte levels, and influencing changes in intracellular volume, which are crucial factors in the toxicity of ASA [29]. So Further research is necessary to elucidate the modest impact of albumin despite its numerous advantageous effects. However, the most unexpected results were demonstrated in the group that received a combination of RL and albumin as they showed the worst results in all investigational parameters compared to the control group and all other treated groups. The authors wonder about these results and the question that needs an answer is why this combination is the worst IV treatment despite administration of every fluid alone is not dangerous. Many previous studies revealed that while colloids are not more efficient than crystalloids in lowering mortality, they remain frequently utilized. This is because colloids stay in the intravascular space longer than crystalloids, making them more effective at maintaining osmotic pressure in a variety of clinical settings [30]. Studies also revealed the safety and effectiveness of colloids vary depending on how long they are in circulation. Colloids with low-to-medium molecular weights, such as albumin, may seep into the interstitial space, but those with higher molecular weights, such as starches, may remain longer. Furthermore, some synthetic colloids are thought to have anticoagulant characteristics or produce other side effects [31]. Numerous studies have examined the comparative impacts of crystalloids versus colloids. However, there is a rarity of research focusing on their combined effects. Some evidence suggests that combining crystalloids and colloids does not confer any discernible advantage.

In a large multicenter trial conducted in 100 intensive care units across Italy, researchers investigated the effectiveness and safety of administering human albumin in addition to crystalloids for the management of severe sepsis with shock. The study aimed to determine whether using albumin alongside crystalloids, rather than crystalloids alone, would enhance survival rates in the intensive care units for patients with severe sepsis at 28 or 90 days. Even though observing amelioration in hemodynamic variables, the researchers assumed that adding albumin to the crystalloid did not offer a survival advantage compared to using crystalloids alone. However, in serious sepsis patients with no shock, the death rate seemed to be higher among those who were treated with both albumin and crystalloids than among those treated with crystalloids alone, although the difference was not statistically significant. The secondary outcomes from the same clinical trials provide a comprehensive assessment of the safety of administering albumin. During severe sepsis. The incidence of new organ failures was similar between the two groups, although the combined albumin crystalloid group exhibited slightly higher average SOFA (Sepsis-related Organ Failure Assessment) scores for liver and coagulation and showed a slightly elevated serum bilirubin level and thrombocytopenia comparable to the crystalloid group. However, the hyperbilirubinemia in the combined albumin and crystalloid group was marginal. The slight decrease in platelet counts may indicate a greater expansion of the intravascular compartment in this group compared to the crystalloid group, resulting in a dilution of hemoglobin content [32].

According to certain studies, administering significant doses of albumin to a euvolemic patient with heart failure, or to a hypervolemic patient, might lead to volume expansion significant enough to contribute to hydrostatic pulmonary edema. However, the increase in oncotic pressure could potentially offer some protection against transalveolar fluid shifts [33]. Additionally, excessive intravenous administration of RL can cause fluid overload, with patients presenting anywhere from mild peripheral edema to respiratory distress due to secondary pulmonary edema [26]. Based on this explanation, administration of combined albumin and RL could potentially result in pulmonary edema, which may account for the impaired pulmonary function observed in the animal group treated with combined albumin and RL [34].

Other Studies also elucidated that an increase in protein-bound salicylate levels can reduce the renal clearance of salicylate, as the freely circulating form is removed via glomerular filtration and tubular secretion [35]. In humans, administering massive intravenous doses of colloid over hours to days has been associated with anuria, which can be resolved with plasmapheresis and reparation of normal plasma colloidal osmotic pressure (known as hyper oncotic renal failure) [36, 37]. This can be due to high plasma colloidal osmotic pressure, which exceeds or matches the effective transglomerular filtration pressure. Consequently, this could explain the unanticipated deleterious effects reported when albumin is mixed with RL.

In another study, Rozich and Paul reported the harmful effect of IV albumin infusion as anuria was observed in a 70-year-old man with a serum albumin of 11.8 g/dL after receiving 1800 g of albumin throughout 72 h. Renal failure was noted when the serum albumin level dropped to 6.6 g/dL. Impaired renal function and continued salicylate absorption could lead to higher salicylate levels and increased toxicity [38]. The current results showed that the renal function tests such as BUN; were significantly increased and the GFR was significantly decreased in the ASA toxic group and this derangement was confirmed by histopathology. The group treated with both RL and albumin showed no significant improvement and the results were nearly the same as the ASA toxic group.

Salicylate poisoning has been shown to affect renal function. A variety of mechanisms have been proposed as possible causes of acute kidney damage (AKI). Elevated body temperature, which causes insensible fluid loss, combined with gastrointestinal fluid losses from vomiting, can result in considerable volume depletion and reduced blood supply to the kidneys (renal hypoperfusion). Furthermore, salicylate-induced nephrotoxicity can take several forms, including acute tubular necrosis, acute interstitial nephritis, papillary necrosis, and proximal tubule dysfunction [39, 40].

Our results are in agreement with the Kellum et al. [41] findings, the author stated that for individuals experiencing acute kidney injury and requiring fluid administration, the current KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommend the use of isotonic crystalloids, and the intravenous fluids should be used with caution to avoid volume overload and interstitial congestion. Other studies have recommended the use of crystalloids ahead of albumin in patients at risk for or with acute kidney injury and advised against the use of hyperoncotic albumin solutions for fluid resuscitation [42]. This may explain the bad outcome of the group treated with albumin and albumin combined with RL or saline on renal function.

In the current study, ASA induced a significant elevation (p < 0.001) in the serum AST and ALT compared to the control group indicating that ASA induced hepatocellular damage. High serum levels of AST and ALT reveal the damage to the liver cell plasma membrane with subsequent leakage of enzymes into the blood [43]. Such biochemical changes may account for the occurrence of histopathological alterations in the livers of ASA-treated rats as shown in Fig. 4b, c; our findings are consistent with El-Ashmawy et al. results [44] that observed lysine acetylsalicylate (LAS) which induced a notable increase in serum levels of ALT and AST. These findings align with the results reported by Vyas et al. [45] which demonstrated a significant elevation in the activities of AST and ALT by aspirin administration. These toxic effects may be attributed to the inhibition of prostaglandin synthesis induced by NSAIDs, which consequently leads to vasoconstriction and diminished organ perfusion. Furthermore, the liver, being a primary organ for drug metabolism, is well-recognized for its heightened susceptibility to drug-induced toxicity [44]. The microsomal system represents another site where salicylates exert their effects, specifically through cytochrome P450-mediated oxidation. Several cytochrome isoforms, such as CYP2C9 and CYP3A4, participate in the oxidative metabolism of various NSAIDs, including salicylates. This metabolic process is implicated in adduct formation, which may contribute to the immune-mediated hepatotoxicity associated with this medication [46]. These consequences were confirmed by the histopathological findings in the examined liver and kidney.

Our results revealed a significant improvement in AST and ALT in the NaCl and RL-treated groups, while the combined albumin and RL-treated group did not show any significant improvement from the ASA toxic group. Our results are consistent with Weiss et al. (2018) which investigated fluid management during acute episodes of liver dysfunction, advocating for the preference of crystalloids over colloids. They recommended the initial use of isotonic saline, with caution to avoid hyperchloremia, and suggested transitioning to RL due to its hypotonicity but the specific role of albumin in acute liver failure patients has not been thoroughly studied [47]. Until now still, no data explained the hepatotoxic effect of the combination of RL and albumin when used in resuscitation.

Finally, the current investigation revealed increased optical density and the strong reaction of NF-kβ immunoreactivity after two successive doses of ASA in the toxic group. An experimental study conducted by Thomas et al. [48] observed an elevation in reactive oxygen species (ROS) levels within the adipocytes of rats following exposure to a concentration of 1 µM of acetylsalicylic acid. Additionally, Thomas observed a concurrent augmentation in lipid peroxidation within the gastric and small intestinal cells of the rats. Consequently, marked and continuing ROS production can activate the transcription factor NF-kβ, leading to elevated transcription of inflammatory cytokines such as interleukin-1 beta, interleukin-8, IL-6, and tumor necrosis factor-alpha [49].

Other evidence elucidated that acidosis has been correlated with inflammation and necrosis. Extracellular acidosis is a danger signal that generates the release of inflammatory cytokines like IL-1β and NF-kβ [50].

Rajamäki et al. [49] demonstrated that resuscitation with RL is associated with a decreased likelihood of metabolic acidosis; this can be attributed to the metabolism of lactate in the liver to bicarbonate. Since local acidification occurs during acute inflammatory processes such as acute pancreatitis, it can be hypothesized that RL aids in preventing the drop in pH, As a result, this could potentially reduce the activation of inflammatory cells and mitigate the intensity of the inflammatory response, which aligns with the findings observed in our study that revealed that RL is highly significant in the improvement of the inflammatory process and reduced level of (NF-kβ). In addition, de-Madaria et al. [51] showed a significant reduction in macrophage activation when cultured with interferon-gamma, lipopolysaccharide, and RL. The administration of RL prevented the transition to an inflammatory phenotype, which is defined by the production of inflammatory cytokines and the inhibition of mannose receptor, C type 1 in macrophages. Furthermore, RL reduced the activation of NF-κB, a key transcription factor implicated in inflammation. This inhibitory action is linked to lactate, as the lack of lactate in Ringer’s solution caused the inhibitory effect to be lost in cell cultures.

Our results revealed there is no beneficial effect when using albumin alone or when combining it with RL in reducing inflammatory markers.