Preventing delayed cerebral ischemia in secured aneurysmal subarachnoid haemorrhage, in an era after the fall of triple-H therapy: a narrative overview for nurses

Approximately 30 % of ASAH patients develop DCI (Sivakumar, and Lazaridis, 2020). DCI usually develops between days three and 21, after ASAH, leading to poor neurologic outcomes (Balasekaran, Soelar, and Anbarasen et al., 2021). A DCI can be symptomatic or asymptomatic; an asymptomatic DCI is evident only in the CT or MRI scan as a region of the new infarct (Udy et al., 2017). Symptomatic DCI is seen as neurologic deterioration manifested by a new focal neurologic deficit such as hemiparesis, neglect, vision changes, apraxia and aphasia, or a drop in Glasgow coma scale by two points, for more than one hour, later in the days after aneurysm repair, to the exclusion of other causes; followed by an area of infarction in the CT or MRI scan (Vergouwen, Vermeulen, and Van Gijn et al., 2010). Cerebral angiography, an ancillary diagnostic tool, might demonstrate arterial narrowing or vasospasm, which is one of the several other causes of DCI (Vergouwen, Vermeulen, and Van Gijn et al., 2010). According to Djilvesi et al. (2020), the therapeutic window of symptomatic cerebral vasospasm is narrow, necessitating prompt diagnosis and management to prevent worse neurologic outcomes. Therefore, it is critical that the bedside nurses exercise caution and closely monitor the ASAH patients during the high-risk period between days three and 21 postictal; the nurses must identify the earliest neurologic manifestations of DCI and escalate to the treating team to help them diagnose and initiate appropriate treatment in time to prevent the long-term effects of DCI.

Previously, DCI was viewed as solely caused by reactive vasospasm triggered by degraded blood byproducts in the subarachnoid space (Schmidt et al., 2022). However, modern diagnostic technology offers a multifactorial perspective on the evolution of DCI (Balasekaran et al., 2021; Schmidt et al., 2022). The current understanding is that DCI results from a de-compensated energy substrate imbalance, where either a poor supply of glucose and oxygen or an excessive unmet demand for these substrates leads to the condition (Schmidt et al., 2022). The insufficient supply of substrates can occur from the macrovascular and microvascular spasms or microthrombi (Schmidt et al., 2022). Conversely, increased demand arises from neuroinflammatory repair processes secondary to early brain injury, such as blood-brain barrier damage, impaired cerebral autoregulation, and cortical spreading depolarisations (Hoh et al., 2023). Fever can also raise metabolic demand (Lavinio, Andrzejowski and Antonopoulou et al., 2023). Djilvesi et al. (2020), using the most advanced high-resolution CT scanner, found that all (100 %) of their 50 participants developed angiographic vasospasm, ranging from mild to severe. They discovered a significant positive correlation (ρ = 0.464, p < 0.01) between cerebral vasospasm severity and the new neurological deficits (Djilvesi et al., 2020). Often, large arterial vasospasms are compensated for by collateral blood flow, leading to asymptomatic vasospasm that may not progress to DCI (Schmidt et al., 2022). Meanwhile, microvascular spasms within a neurovascular unit may pose a challenge to treatment, progressing to DCI (Schmidt et al., 2022). This complex pathophysiology highlights the critical requirement to maintain normoglycemia, normoxia and normothermia alongside neurological observations in ASAH to prevent DCI.

Nimodipine is a calcium channel blocker (L-type) with an anticipated vasodilatory action on cerebrovascular smooth muscle (Burrell et al., 2016; Hoh et al., 2023). Interestingly, the vasodilatory effect of Nimodipine is not demonstrated in angiographies (Burrell et al., 2016). However, it offers some neuroprotective effects, securing its spot in the latest AHA/ ASA guidelines (Hoh et al., 2023). It is postulated that nimodipine’s neuroprotective effect is attributed to its ability to prevent toxicity from calcium ion influx into neurons and neuronal death (Sandow et al., 2016). Furthermore, nimodipine promotes fibrinolytic activity, reducing the microthrombi and suppressing the cortical spreading depolarisations that cause ischemia (Rass, Kindl, and Lindner et al., 2023).

The evidence for the use of prophylactic Nimodipine to prevent DCI comes from that generated more than three decades ago (Pickard, Murray, and Illingworth et al., 1989); despite its unclear mechanism of action (Sandow et al., 2016). Following the pioneering research of Allen et al., (1983), Pickard and colleagues tested the effect of enteral Nimodipine in preventing DCI in an RCT(n=554) in 1989 (Pickard et al., 1989); in this pivotal work, they could demonstrate a significant reduction (34 %) in the development of infarct (p= 0.003, 95% CI= 13–50) and a significant decrease in the poorer outcome by 40 % (p< 0.001, 95% CI= 20–50) (Pickard et al., 1989). Although the above results were statistically significant, the wide confidence interval (CI 20–50) might suggest the possibility of inconsistent results when using Nimodipine, which warrants a critical approach to its application. Nevertheless, enteral Nimodipine has become a standard inclusion in the management of ASAH to prevent DCI in many guidelines (Hoh et al., 2023). However, some guidelines, for instance, the NICE guideline, extended only a weaker recommendation for enteral Nimodipine due to poor supporting evidence (NICE, 2022). Nonetheless, bedside nurses who implement medical decisions administer the Nimodipine tablets whole or crushed, depending on the patient’s neurological status and ability to ingest them safely (Isse, Abdallah, and Mahmoud, 2020; Mahmoud, Hefny, and Panos et al., 2023; Pickard et al., 1989).

The most recent studies aim to find the efficacy of whole Nimodipine administered orally versus crushed Nimodipine given through the feeding tube. Isse et al. (2020) investigated the effectiveness of whole versus crushed Nimodipine in a retrospective observational study (ROS) (n=727) and reported increased odds of DCI in the crushed Nimodipine group (OR 8.9, 95% CI 1.1–73.1, p= 0.042). Later, Mahmoud et al. (2023) conducted a similar ROS (n=727) using a regression model to find the effect of various nimodipine formulations and administration techniques on DCI; they identified that crushed Nimodipine tablets and extracted Nimodipine from the capsules were related to higher odds of DCI (OR 6.66, 95% CI 3.48–12.74, p <0.0001 and OR 3.92, 95% CI 2.05–7.52, p <0.0001, respectively). The above two studies indicate a possible reduction in the bioavailability of Nimodipine, contributing to a higher incidence of DCI. Postulated aetiologies for the reduced bioavailability of Nimodipine are intrinsic factors, technical inaccuracies, or both. Impaired gastrointestinal motility in ill patients is an example of an intrinsic factor that can contribute to lower Nimodipine bioavailability (Isse et al., 2020). On the other hand, technical inaccuracies may include the drug content loss during crushing, photo-oxidation of light-sensitive Nimodipine stored incorrectly, or delayed administration of the prepared Nimodipine, and drug and food interactions (Mahmoud et al., 2023). Furthermore, enteral Nimodipine’s half-life is brief, requiring punctual administration every two to four hours to maximise its effect (Isse et al., 2020). Therefore, it is imperative that nurses administering Nimodipine enterally protect the tablets from light, space the potentially interacting substances or drugs with Nimodipine, prevent drug loss during crushing or extraction, and administer immediately once prepared on time to maximise the drug bioavailability and thereby prevent DCI.

The Neurocritical Care Society guideline (2023) and the AHA/ ASA guideline (2023) do not recommend the prophylactic use of intravenous Nimodipine (Hoh et al., 2023; Treggiari et al., 2023). Furthermore, the number of studies investigating the effect of intravenous Nimodipine following ASAH is limited. According to the MANTRA survey (2024), an international clinical practice survey to identify, monitor and manage strategies for cerebral vasospasm-associated DCI in ASAH, intravenous Nimodipine administration remains a practice in some intensive care units (ICU) (Picetti, Bouzat, and Bader et al., 2024). The concern around Intravenous Nimodipine dose compared to its enteral counterparts is the higher risk of precipitating arterial hypotension, which could lead to DCI (Moser, Rössler, and Hirschmann et al., 2025). Cardiovascular monitoring must occur while patients receive intravenous Nimodipine to identify and treat arterial hypotension (Göttsche, Schweingruber, and Groth et al., 2024).

Empirically, it is believed that the magnitude of cerebral hypoperfusion in the initial hours of ASAH determines the extent of early brain injury, the risk of DCI, and the prognosis (Hofmann, Donaldson, and Fischer et al., 2023). Without any brain insult, the normal cerebral autoregulatory function ensures a steady cerebral blood flow (CBF) over a range of cerebral perfusion pressures (Burrell et al., 2016; Silverman, Kodali, and Strander et al., 2019). Cerebral perfusion pressure is the gradient that drives oxygen and nutrients to the brain, ensuring adequate cerebral blood flow (Hickey, 2014). Cerebral autoregulation is the ability of the cerebral blood vessels to dilate and constrict to maintain a stable CBF during fluctuations in systemic blood pressure and meet metabolic demands (Hickey, 2014). However, during early brain injury after ASAH, the cerebral autoregulation becomes dysfunctional, allowing the systemic blood pressure to influence the CBF linearly, especially in higher-grade ASAH (Hofmann et al., 2023; Murphy et al., 2017). Mean arterial pressure (MAP) is the average pressure in a person’s arteries during one cardiac cycle. During dysfunctional autoregulation, the higher the MAP, the higher the cerebral perfusion pressure and CBF will be, and vice versa (Burrell et al., 2016).

The above idea of MAP-dependent CBF in the wake of dysfunctional cerebral autoregulation in ASAH was tested in a few studies. Murphy et al. (2017) conducted a smaller ROS to investigate the effect of induced hypertension (IH) on mean transit time (MTT) and the CBF in patients with DCI; the Mean transit time (MTT) is the average time it takes for blood to pass through the brain’s capillary network from arterial inflow to venous outflow. Murphy et al. reported a shorter MTT after inducing hypertension in the immediate days following ASAH compared to the subsequent period (p = 0.005) (Murphy et al., 2017); this implies a MAP-dependent CBF in the setting of dysfunctional cerebral autoregulation in the early post-ictal phase. Later, in a similar ROS (n = 134), Hofmann et al. found that MTT was longer when the MAP was low and vice versa (p = 0.042) (Hofmann et al., 2023). Although CBF and volume are considered in calculating MTT (Murphy et al., 2017), interestingly, reports from the above studies show only insignificant improvement in CBF with induced hypertension; this could be attributed to the smaller sample sizes and the characteristics of the study population itself, which included patients already in DCI. Hence, further investigations are required to establish the correlation between the induced hypertension, MTT and CBF in ASAH and their role in preventing DCI.

Nevertheless, the literature suggests that hypovolemia is a risk factor for the development of DCI (Hofmann et al., 2023; Joffe et al., 2015; Murphy et al., 2017; Vergouw et al., 2020). Similarly, prolonged MTT is an observed feature in DCI (Murphy et al., 2017). Hence, preventing hypotension is of utmost importance in maintaining adequate cerebral perfusion in the light of impaired cerebral autoregulation in ASAH, for a better neurological outcome. Therefore, closely monitoring blood pressure for hypotension—along with other influencing factors such as medications that can induce hypotension, poor fluid intake, negative fluid balance, and comorbidities like sepsis—and promptly intervening and seeking medical attention as appropriate can be prudent nursing strategies to prevent DCI.

Medically induced hypertension used to be a common practice as a part of Triple-H therapy to prevent DCI once the aneurysms are secured; however, it has fallen out of favour in the latest guidelines published by the NICE, AHA/ ASA, and Neurocritical Care Society due to the insufficient evidence (Hoh et al., 2023; NICE, 2022; Treggiari et al., 2023). Although NICE does not approve prophylactic blood pressure augmentation to prevent DCI, they recommend treating an episode of DCI with euvolemia and vasopressor agents (NICE, 2022).

The purpose of fluid management in secured ASAH is to optimise the intravascular or circulatory blood volume (Joffe et al., 2015). Unfortunately, in clinical practice, hypervolemia is an undesirable and ill-recognised aetiology of brain damage frequently resulting when striving to correct hypovolemia or achieve a positive fluid balance (Vergouw et al., 2020). Joffe et al. (2015) conducted prospective observational research (n=39) to investigate the effects of different amounts of prophylactic crystalloid infusion on circulating blood volume; group one (n=20) received 30ml/kg/day aiming euvolemia, while group two (n=19) received 60ml/kg/day targeting hypervolemia (Joffe et al., 2015). Surprisingly, they found that the additional infusion above the euvolemic goal had no significant effect on expanding the circulating blood volume (p =0.8); instead, it increased the cumulative fluid balance (Joffe et al., 2015). Furthermore, any additional fluid input that exceeds the euvolemic status is either excreted later as urine, leading to diuresis or retained in the extravascular spaces (Lennihan et al., 2000; Vergouw et al., 2020). More evidence reporting the unfavourable effects of attempting hypervolemia is from an extensive (n=246) ROS by Vergouw et al. (2020); group one (n1=223) received higher fluid input during the first 72 hours of secured ASAH, whereas group two (n2 =23) received haemodynamic monitoring-guided, goal-directed fluid input (Vergouw et al., 2020). Although the retrospective nature of the above study may have limited control over the confounders, the results were similar to those of the seminal RCT that refuted the hypervolemic component of triple-H therapy (Lennihan et al., 2000). Vergouw et al. found that high cumulative fluid input in the first 72 hours was related to a higher incidence of DCI (OR=1.19/ litre, 95% CI=1.07–1.32) (Vergouw et al., 2020). The underlying pathophysiology of DCI development in the ictal phase from hypervolemia is unclear, although a few causes have been postulated; these include damage to the blood-brain barrier from reduced shear stress, higher impedance to oxygen diffusion due to cerebral oedema, and reduced oxygen-carrying capacity of blood secondary to lower haemoglobin levels from haemodilution (Vergouw et al., 2020). The other systemic complications of induced hypervolemia reported in the literature are congestive cardiac failure, hypoxemic respiratory failure and renal injury (Lennihan et al., 2000; Sivakumar and Lazaridis, 2020). Since the excessive fluid input after the euvolemic state does not contribute to a persistent increase in the circulating blood volume or CBF, but to complications, it is prudent to aim for euvolemia in ASAH to prevent ill effects, including DCI.

Despite euvolemia being the cornerstone in the medical management of ASAH, ascertaining fluid status is a nuanced concept and problematic in both medical and nursing practice (De Winkel et al., 2021; Hoff, Rinkel, and Verweij et al., 2008; Joffe et al., 2015; Vergouw et al., 2020). Euvolemia is a state of normal blood volume within the blood vessels, ensuring adequate tissue perfusion without fluid overload or deficit (Joffe et al., 2015). The notion of euvolemia as a management goal is highly subjective, leading to intuition-based fluid management and unwarranted complications from fluid volume expansions (Vergouw et al., 2020). Joffe et al. (2015) measured circulating blood volume indirectly using injected radioisotope and demonstrated a variation in the actual circulating blood volume between the study groups named euvolemia and hypervolemia groups (OR=0.8, 95% CI 0.13–4.9). While about half of the patients in both groups attained a euvolemic state, the other half remained hypovolemic (Joffe et al., 2015). It implies a dynamic nature of intravascular volume status and a requirement for validated tools to assess fluid status continuously at the bedside. Furthermore, it warrants a more judicious individualised approach in fluid management during the initial days of ASAH when the risk of vasospasm and DCI is high (Joffe et al., 2015).

A relatively new and promising concept is the Goal-directed fluid management (GDFM) in ASAH to prevent DCI. Anetsberger, Gempt, and Blobner (2020) conducted a prospective RCT on 108 patients with ASAH. In this study, patients were randomly assigned to the control group (n1 = 54) and the GDFM group (n2 = 54) (Anetsberger et al., 2020). Those patients were cared for in the ICU for 14 days, and they had advanced invasive haemodynamic monitoring, including transpulmonary thermodilution to guide fluid therapy aiming for euvolemia (Anetsberger et al., 2020). The GDFM group showed reduced incidence (13%) of DCI compared to the control group (32 %) (odds ratio, 0.324 (95% CI, 0.11–0.86, P=0.021) (Anetsberger et al., 2020). The authors of this study attributed the reduced incidence of DCI in the GDFM group to the timely volume correction to euvolemia (Anetsberger et al., 2020). Ironically, not all ASAH patients are managed in the ICU with an invasive haemodynamic monitoring system, which makes timely fluid correction difficult; hence, the practical application of GDFM to prevent DCI is currently limited to ICU settings, despite maintaining euvolemia being a desirable strategy for every ASAH patient during the high-risk period.

The literature indicates that nursing practices need to be updated to reflect current evidence. Hoff and colleagues (2008) conducted a prospective cohort study to test the ability of experienced nurses to predict fluid statuses (n =350) in ASAH patients. Their predictions were compared to the actual circulating blood volume determined by the pulse dye densitometry technique (Hoff et al., 2008). The participating nurses could use the heart rate, blood pressure, urine output, fluid balances, central venous pressure, and peripheral oedema to make predictions (Hoff et al., 2008). Interestingly, the nurses’ fluid status predictions did not correspond to the actual results measured (Hoff et al., 2008); the predicted hypovolemia showed a sensitivity of 0.10 (95%CI = 0.06 to 0.16), and the positive predictive value was 0.37 (95%CI = 0.23 to 0.53) (Hoff et al., 2008). Unfortunately, the patient’s medical history, physical examination, fluid balance monitoring, vital signs, serum sodium levels and body weight do not provide a reliable indication of circulating blood volume but may indicate the extracellular fluid status (Joffe et al., 2015). Therefore, caution must be exercised when interpreting the fluid status from the above parameters when managing patients with ASAH. Moreover, a qualitative study surveying 145 neurosurgical centres across five continents demonstrated widespread variability in the range of fluid balance considered as euvolemia (De Winkel et al., 2021); although in reality, the euvolemic statuses correspond to the circulating blood volume, some centres considered a fluid balance of zero as euvolemia, while the others considered a positive fluid balance of 250 to 500 ml as euvolemic state (De Winkel et al., 2021). Considering the higher significance of euvolemia in the management of ASAH and widespread discordance in fluid status assessment practices, these studies reiterate the paramount need to adopt some advanced technique at the bedside to assist fluid status assessments. In the meantime, it is advisable to continue following the organisational guidelines on monitoring and managing the fluid statuses.

The lack of validated tools to assess euvolemia in the management of ASAH remains a real problem (Hoff et al., 2008); it could potentially risk the patient to DCI. Kasuya, Onda, and Yoneyama, et al. (2003) on recognising the significance of circulating blood volume in the management of ASAH, studied the changes in circulating blood volume utilising a technology called pulse spectrometry in ASAH; in this germinal research (n =50), they concluded that pulse spectrometry is a promising, powerful tool that could be used in the management of ASAH (Kasuya et al., 2003). Since then, the technology has advanced, and modern pulse oximeters with the co-oximetry technique have evolved (Van Genderen, Lima, and Bezemer et al., 2013); they can calculate the peripheral perfusion index (PPI), a surrogate of circulating blood volume, from the non-pulsatile and pulsatile peripheral blood flow that denotes the autonomic nervous system activity and the cardiac output (Van Genderen et al., 2013). According to Van Genderen et al., a lower PPI compared to the patient’s baseline value can flag the onset of central hypovolemia or low circulating blood volume much before the start of cardiovascular decompensation (Van Genderen et al., 2013). However, extensive research is essential to validate the utility of PPI in GDFM.

The application of PPI in GDFM is being trialled in the management of septic shock (Van Genderen, Engels, and Van der Valk et al., 2015), to predict central hypovolaemia in awake healthy volunteers (Van Genderen et al., 2013), fluid responsiveness in critically ill patients (Narayanan, Rao, and Kandasamy et al., 2025), and so on, with promising results. Whilst all these studies were conducted in entirely different settings and cohorts to guide GDFM, it reminds us of a possible application of a cost-effective and widely accessible, simple, non-invasive gadget that the nurses can operate with less extensive training; yet potentially high-impact strategy in the more accurate measurement of euvolemia in preventing hypovolemia and DCI. Nevertheless, the scope of PPI in bedside monitoring of intravascular fluid status in ASAH was not explored much after a small, promising study by Kasuya and colleagues in 2003. Suppose future research could prove PPI as an applicable tool in the GDFM in ASAH; in that case, nurses may be able to use it as an adjunct tool at the bedside in the more accurate assessment of fluid status for preventing DCI, given that the current methods are ambiguous and futile.

Maintaining normoxia is another emerging topic of interest for nurses in preventing DCI. The findings from the most available studies demonstrate that hyperoxia in the acute phase of ASAH is associated with the development of DCI (Ahn et al., 2022; Robba, Battaglini, and Cinotti et al., 2023; Yokoyama, Minamino, and Hifumi et al., 2019). It is postulated that hyperoxia exposes the brain to excessive reactive oxygen species, compounding the effects of deranged cellular respiration in ASAH (Ahn et al., 2022; Fukuda, Koga, and Suehiro et al., 2021; Reynolds et al., 2021; Robba et al., 2023). Additionally, hyperoxia is thought to promote the oxidation of cell-free haemoglobin in the subarachnoid space, generating a potent ‘spasmogen’ that can trigger cerebral vasospasm (Reynolds et al., 2021). Furthermore, hyperoxia overwhelms the brain’s antioxidant system, contributing to oxidative neuronal damage, neuronal death, disruption of the blood-brain barrier, and decreased cerebral perfusion (Ahn et al., 2022; Fukuda et al., 2021). Similarly, it is also suggested that hyperventilation and hypocapnia may induce cerebral vasoconstriction, compromising CBF (Ahn et al., 2022). Therefore, the growing research advocates the maintenance of normoxia in victims of ASAH to prevent DCI and for improved neurological outcomes, although further prospective high-quality research is warranted.

The specific threshold value of hyperoxia in ASAH is still uncertain (Robba et al., 2023). Interestingly, the literature indicates that the threshold of hyperoxia may vary between different subtypes of brain injury, such as traumatic brain injury, ASAH and so on, challenging the assignment of a universal number for hyperoxia (Robba et al., 2023). Despite supplemental oxygen being considered a drug, multiple studies indicate that its use tends to remain ubiquitous in neurocritical care settings (Reynolds et al., 2021; Yokoyama et al., 2019). While the reason for continued use of supplemental oxygen is occasionally attributed to the pending evaluation to wean oxygen, instances of prophylactic usage of supplemental oxygen to prevent hypoxia are also not uncommon (Fukuda et al., 2021). According to Raynolds et al. (2021), in their retrospective study, they tested the relationship between the incidence of cerebral vasospasm and hyperoxia (n = 310); they found a dose-related increase in the incidence of cerebral vasospasm (p = 0.019) within the first 72 hours postictal. Interestingly, this study cohort revealed the prevalent practice of loose titration of low to moderate amounts of supplemental oxygen in their setting, resulting in supratherapeutic levels of partial pressure of arterial oxygen in many patients (Reynolds et al., 2021). Although recent research identifies hyperoxia as a modifiable risk factor in preventing DCI, unfortunately, we lack an assigned parameter that defines hyperoxia in ASAH. Hence, further prospective controlled studies investigating oxygen management in ASAH are urgently required to inform nurses and medical practitioners working to prevent DCI.

Targeted temperature management in ASAH is another evolving area of study. Neurogenic fevers after the brain insult could increase the brain’s metabolic demand, promote secondary brain injury, precipitate DCI and worsen the neurologic outcome in ASAH patients (Lavinio et al., 2023). Targeted temperature management controls the core body temperature using automated feedback-controlled devices (Lavinio et al., 2023). It induces hypothermia, maintains hypothermia and rewarms slowly (Lavinio et al., 2023; Liu, Li, and Han et al., 2024). However, the evidence from those studies is insufficient, and more extensive randomised controlled trials must confirm their safe applicability.

In nursing practice, preventing DCI in patients with ASAH requires vigilant monitoring, early intervention, and evidence-based care strategies. Nurses play a critical role in assessing neurological status, vital signs, blood sugar levels and fluid balance; they should ensure normotension, normothermia, normoglycemia, normoxia, euvolemia, and provide timely administration of enteral nimodipine in correct doses, minimising drug and food interactions. Close collaboration with the interdisciplinary team is essential to implement protocols for early detection and management of complications. Additionally, patient and family education on recognising symptoms and adhering to follow-up care can improve outcomes and reduce the burden of DCI in ASAH patients.