Organ-specific malperfusion in acute type A aortic dissection: epidemiological meta-analysis of incidence rates

Abstract

Background

Acute type A aortic dissection is a life-threatening clinical emergency that necessitates immediate surgical intervention with an estimated mortality rate of approximately 1–2% per hour. When complicated by malperfusion, the perioperative mortality rate is reported to be increased by up to 39%. Malperfusion can affect many vascular beds with varying incidence and severity, resulting in coronary, cerebral, visceral, peripheral, renal or spinal malperfusion. The primary aim of this systematic review and meta-analysis is to investigate the epidemiology of specific types of organ malperfusion in acute type A aortic dissection and to analyse the impact on the survival outcomes associated with each malperfusion type.

Methods

Electronic databases PubMed, MEDLINE and Embase were searched through to September 2024 to identify original studies that presented data on the incidence and the survival outcome of organ malperfusion in association with acute type A aortic dissection. The extracted data included patient characteristics and incidence of organ-specific malperfusion. Primary outcomes were the respective in-hospital mortality rate associated with each organ-specific malperfusion and a proportional meta-analysis was conducted to pool results. Quality assessment was performed using the modified National Institutes of Health quality assessment tool for single-arm observational studies.

Results

A total of 40 studies met the inclusion criteria, including a total of 35 361 patients. Peripheral limb malperfusion was the most prevalent with a pooled incidence of 12% (95% c.i. 10 to 14). This was followed by lower limb or iliofemoral with 11% (95% c.i. 9 to 14). Spinal malperfusion was the lowest with 1% (95% c.i. 1 to 2). The pooled mortality rate with organ malperfusion varied between 18 and 36%. Within this population the highest mortality rate was associated with mesenteric malperfusion with 36% (95% c.i. 28 to 45). Following this the highest mortality rate was found with coronary at 33% (95% c.i. 26 to 40) and cerebral at 28% (95% c.i. 24 to 33) malperfusion.

Conclusion

Survival during hospital admission after acute type A aortic dissection can vary depending on the presence and type of malperfusion, with mesenteric, coronary and cerebral malperfusion being associated with the highest in-hospital mortality rates. Organ-specific malperfusion syndromes should be considered when assessing the perioperative risk and surgical planning of patients undergoing surgical repair for acute type A aortic dissection.

In this epidemiological investigation, the study reports significant variation in the rates of organ-specific malperfusion among acute type A aortic dissection patients, with cerebral and coronary malperfusion occurring in approximately one in every ten patients presenting with acute type A aortic dissection. This data highlights the importance of considering specific malperfusion types when treating acute type A aortic dissection patients, aiding vigilant decision-making and surgical planning.

Introduction

Acute type A aortic dissection (ATAAD) is a life-threatening clinical emergency that necessitates immediate surgical intervention. The estimated mortality rate without surgical repair is approximately 1–2% per hour, with a mortality rate of 50% in the first 24 h^1,2. Multiple preoperative factors are recognized to affect outcomes in patients undergoing surgery for ATAAD. End-organ ischaemia is a sequelae of aortic dissection which can result in malperfusion syndrome³. When present, malperfusion can increase the mortality rate by 3–4-fold in patients with ATAAD⁴. Norton et al. showed that in patients with preoperative malperfusion, the perioperative mortality rate is reported to be increased by up to 39%⁵.

Malperfusion can be defined as compromised blood flow in one or more organs resulting in ischaemia and end-organ dysfunction as a consequence of dissection-related obstruction of the aorta and its branch vessels^3,5. This can affect many vascular beds, some of which include coronary, cerebral, visceral, peripheral, renal or spinal malperfusion, with varying incidence and severity⁶. The Penn classification is a validated classification system to predict the severity of malperfusion. A strong association has been found between different Penn classes and early mortality rates in patients presenting with ATAAD⁷.

Despite recent innovations in current perioperative anaesthetic and surgical practice, this high-risk patient cohort is associated with suboptimal outcomes^3,4. While several studies have reported clinical outcomes in this group of patients, there is limited evidence on the respective incidence of each organ malperfusion in patients presenting with ATAAD.

The primary aim of this systematic review and meta-analysis is to summarize the epidemiology and incidence of specific types of organ malperfusion in ATAAD as well as to analyse the impact of each malperfusion type on survival outcomes.

Methods

Literature search

The search strategy was developed using the Population, Intervention, Comparator and Outcome (PICO) framework, with the aim of identifying relevant studies reporting the incidence of different organ malperfusion associated with ATAAD and the respective survival outcome associated with each type of malperfusion. The search was carried out across various databases, including PubMed, MEDLINE and Embase, covering the interval from inception up to April 2023. The search process adhered to the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and the recommended guidelines⁸. The specific search terms used were (‘malperfusion’ OR ‘Penn’) AND (‘type A aortic dissection’). Studies meeting the predetermined criteria were chosen for analysis, following the application of both inclusion and exclusion criteria during the stages of title-abstract and full-text screening. Screening of the literature was updated in September 2024 using the same search terms. A quality assessment using the modified National Institutes of Health quality assessment tool for single-arm observational studies was performed.

Inclusion and exclusion criteria

The primary criteria for inclusion consisted of studies that presented data on the incidence and the survival outcome of organ malperfusion in association with ATAAD. In order to be included, the following conditions had to be met: the research design needed to be either clinical trials or observational studies, the study had to involve human subjects with a minimum of 20 patients and the participants had to be adults. On the other hand, exclusion criteria were: review articles, case reports, editorials, study protocols, commentaries or letters, and studies not published in English. Throughout both the evaluation of abstracts and full-text screening, two evaluators worked independently to assess each study against the eligibility criteria. If any discrepancies or differences arose, a third reviewer was consulted to resolve them. The stepwise approach from the initial literature search to the ultimate selection of studies is visually represented in Fig. 1, displayed in the PRISMA flow chart.

Fig. 1.

PRISMA flow chart highlighting the detailed steps of study selection

Data extraction and outcomes

After meeting the inclusion criteria, each article was initially extracted by one reviewer and then revised by another reviewer. The extracted results were compared, and any discrepancies or disagreements were resolved through discussion and consensus among the reviewers. The extracted data included the characteristics of the included studies, as well as the incidence of organ-specific malperfusion and the respective in-hospital mortality rate associated with it. The endpoint for this analysis was the incidence rate of specific organ malperfusion associated with ATAAD and the respective mortality rate associated with each type.

Statistical analysis

This meta-analysis followed the guidelines provided by the Cochrane Collaboration and the Meta-analysis of Observational Studies in Epidemiology and Proportional Meta-Analyses of incidence and prevalence^9,10. The statistical analysis was carried out using STATA software v. 8 (StataCorp LLC: College Station, TX, USA). To combine the incidence rates and mortality rates linked with different types of malperfusion in ATAAD, a proportional meta-analysis was executed. The Freeman–Tukey double arcsine transformation was employed to stabilize the variance of the proportions reported in each study. Random pooled effects using a restricted estimated maximum likelihood model were computed, accompanied by their respective 95% confidence intervals (c.i.). To quantify statistical heterogeneity, the Q-test for heterogeneity (as proposed by Cochrane in 1954)⁸ and I² statistics were utilized.

Results

Included studies

Of 1612 studies identified during the initial search, 40 studies that reported at least one type of organ malperfusion associated with ATAAD and its respective mortality rate were included^11–50 (Table S1). The total number of patients in the included studies added up to 35 361 patients with ATAAD. Figure 1 shows the PRISMA flow chart highlighting the process of filtering the included articles. A total of 30 studies were of good quality and 11 were of moderate quality (Table S2).

Organ-specific incidence of malperfusion

Coronary artery malperfusion was found in 10% of patients (95% c.i. 8 to 12), while cerebral malperfusion occurred in 10% (95% c.i. 9 to 12). Further, any limb malperfusion affected approximately 12% of patients (95% c.i. 10 to 14), closely followed by specific lower limb or iliofemoral malperfusion at 11% (95% c.i. 9 to 14). In contrast, spinal malperfusion had the lowest incidence at just 1% (95% c.i. 1 to 2). Mesenteric malperfusion, on the other hand, had the highest mortality rate, but its incidence was relatively low compared with other organ systems, standing at 6% (95% c.i. 4 to 8). The pooled incidence of each organ malperfusion is illustrated in Table 1 and Supplementary Figs. S1–S7.

Table 1.

The incidence of organ-specific malperfusion and the associated in-hospital mortality rate

Organ malperfusion	Pooled incidence (95% c.i.)	Pooled specific mortality rate (95% c.i.)
Coronary	0.10 (0.08,0.12)	0.33 (0.26,0.40)
Cerebral	0.10 (0.09,0.12)	0.28 (0.24,0.33)
Mesenteric	0.06 (0.04,0.08)	0.36 (0.28,0.45)
Peripheral limb	0.12 (0.10,0.14)	0.23 (0.17,0.30)
Lower limb or iliofemoral	0.11 (0.09,0.14)	0.23 (0.12,0.35)
Renal	0.05 (0.03,0.07)	0.21 (0.13,0.31)
Spinal	0.01 (0.01,0.02)	0.18 (0.07,0.32)

Mortality rates in the presence of organ malperfusion

The pooled mortality rates associated with organ malperfusion ranged from 18 to 36%. The highest mortality rate was observed in the presence of mesenteric malperfusion, reaching 36% (95% c.i. 28 to 45). Following closely, the second-highest mortality rate was associated with coronary malperfusion at 33% (95% c.i. 26 to 40), followed by cerebral malperfusion with a mortality rate of 28% (95% c.i. 24 to 33). In contrast, the presence of spinal malperfusion was associated with a comparatively lower average mortality rate of around 18% (95% c.i. 7 to 32).

Discussion

Despite contemporary advances in the perioperative anaesthetic and surgical management of ATAAD, preoperative organ malperfusion is associated with adverse immediate and long-term outcomes. Data reported by multiple studies have described a strong correlation between the number of malperfused organs and early death^43,45. Pacini et al. previously reported that patients presenting with any malperfusion syndrome had a markedly increased mortality rate compared with those without malperfusion (43.7% versus 15% respectively, P = 0.001). Mortality rates increased with the number of organ involvement of one, two or greater than two organ malperfusions (34.7%, 61.9% and 85.7% respectively)⁴³.

One of the most serious complications of ATAAD is preoperative coronary malperfusion⁴⁰. As cardiac perfusion is heavily dependent on the satisfactory morphology of coronary arteries, static or dynamic obstruction to the coronary blood flow can undoubtedly lead to myocardial ischaemia^39,51. Timely restoration of coronary blood supply to the myocardium is necessary for patient survival³⁹. In these results, the pooled incidence of coronary malperfusion was 10%, and when present, the in-hospital mortality rate averaged 33%. Coronary malperfusion is also associated with adverse long-term outcomes. Girdauskas et al. and Kawahito et al. reported 22% and 24.5%, respectively, patient survival at 5-year follow-up in the coronary malperfusion patient cohort^12,52. The reasoning behind this high mortality rate can possibly be explained by technical difficulties during preoperative percutaneous coronary intervention (PCI), resulting in suboptimal early revascularization outcomes⁴⁰. Nonetheless, the presence of other organ malperfusions is a major confounder in such results. A study by Nakai et al. suggested that operating in this patient cohort within 5 h of symptom onset significantly improved their long-term outcomes, and suggested reconsidering performing coronary intervention before central repair⁴⁰.

Several studies have recommended using an early reperfusion strategy with emergency PCI as a bridge to surgical repair, especially when the left coronary artery is involved^16,29,53. Endovascular stenting before cardiac surgery can potentially reduce the rates of postoperative myocardial injury, however, it is important to weigh this against the risk of delaying surgery³¹. Another study by Tong et al. elegantly described that a flexible surgical approach based on lesion classification is important for optimal outcomes, where Neri type A and most type B lesions can adequately be repaired with an orifice or supra coronary repair, Neri type C lesions can undergo coronary artery bypass graft (CABG) and the management of coronary orifice intimal tear lesions should be individualized^39,54,55. However, if the dissection extends to the distal coronary artery, CABG is preferable to direct coronary repair as it can be challenging/risky to mobilize and repair acutely dissected coronary arteries^52,56. Intraoperatively, myocardial protection can be carried out using intermittent antegrade and retrograde cold blood cardioplegia via the coronary ostium and coronary sinus respectively⁴⁵. In the context of potential previous coronary artery disease and/or reduced coronary flow secondary to the aortic dissection which can extend to the coronary arteries, delivery of antegrade cardioplegia alone may result in inadequate distribution, compromising myocardial protection⁵⁶.

Cerebral malperfusion in ATAAD can occur due to multiple reasons, some of which include partial/complete occlusion of the arch vessels by the intimal-medial flap, hypoxic encephalopathy secondary to shock or tamponade and/or brain embolism from thrombus in the false lumen³⁷. The results from this meta-analysis report a pooled incidence of 10% in ATAAD patients with an associated in-hospital mortality rate of 28%. The primary goal of surgical repair is to prevent stroke or coma, which are the main causes of early death in patients with cerebral malperfusion⁴⁵. The principles of surgery for brain protection involve antegrade cerebral perfusion (ACP) with circulatory arrest of the lower body. Additionally, deep hypothermic circulatory arrest (DHCA) has traditionally been the adjuvant procedure during arch reconstruction. Alongside that, retrograde cerebral perfusion (RCP) might also be used⁴². Whilst some studies report that patients who underwent ACP experienced reduced transient neurological dysfunction, attempts to minimize the duration of circulatory arrest of the brain with RCP or DHCA had comparable clinical outcomes to ACP in relation to stroke incidence and mortality rates^57,58.

Several studies have reported a significantly lower 5–10-year survival rate in patients who had preoperative cerebral malperfusion^32,59. Some studies have also reported a higher incidence of new neurological deficits following surgery in patients with preoperative cerebral malperfusion³². Specifically, elderly patients are at a higher risk of developing adverse cerebrovascular postoperative complications, as they are more susceptible to the cerebral insult from DHCA⁶⁰. Consequently, elderly patients are more likely to suffer from physical limitations, compared with younger individuals, which have an impact on their quality of life⁶⁰. Since cerebral ischaemic time is a key factor in the recovery of patients with cerebral malperfusion undergoing operative repair, surgical approaches should aim to minimize the duration of ischaemia²⁶.

In this pooled analysis, preoperative mesenteric malperfusion was present in 6% of patients and its presence was associated with the highest (36%) in-hospital mortality rate; this remains consistent with previous studies^35,44. Unlike coronary or cerebral ischaemia, mesenteric ischaemia frequently lacks early clinical symptoms and may be overlooked. Severe acidosis and hyperlactaemia present as advanced signs of mesenteric malperfusion and are associated with a poor prognosis^44,61. Whilst the goal of emergency ATAAD surgery is to prevent death secondary to aortic rupture, patients with mesenteric malperfusion are at a greater risk of dying from organ failure (bowel necrosis and septic shock), which may be more imminently life-threatening⁶². Yang et al. reported that in patients with mesenteric malperfusion syndromes, the fatality risk from organ failure was 6.6 times greater than the risk of death from aortic rupture⁶³. Patients presenting with lower extremity malperfusion often associated with a primary entry tear in the aortic arch or proximal descending aorta were usually in a more critical condition, requiring additional and more extensive repair as central repair alone is insufficient to resect the primary entry tear^33,64.

In 1996, investigators at The University of Michigan first adopted a new approach of managing ATAAD patients with mesenteric malperfusion using percutaneous endovascular revascularization via fenestration/stenting of the critically malperfused visceral branch vessels, followed by delayed central open aortic repair. In a recent study, they concluded that although the in-hospital mortality rate was significantly higher in the mesenteric malperfusion cohort, the postoperative long-term 10-year survival in the mesenteric malperfusion cohort achieved favourable outcomes and was not significantly different from that in the non-malperfusion cohort^62,63. Similarly, investigators at Emory University describe a surgical strategy using thoracic endovascular aortic repair followed by delayed ascending/arch replacement⁶⁵. Patel et al. evaluated the outcomes of initial percutaneous intervention of various vascular beds followed by delayed operative repair; 33% of patients died following hospital admission before undergoing surgical repair⁶⁶. Therefore, the benefits of endovascular stenting before cardiac surgery should be weighed against the risk of delayed surgical repair⁶³. In patients with mesenteric malperfusion and features of ischaemic end-organ dysfunction (acute stroke, intestinal necrosis or serum lactate ≥6 mmol/l), a staged approach should be considered if they are stable (no features of aortic rupture or cardiac tamponade)^31,62,63. Mesenteric or celiac bypass, temporary active perfusion, hybrid endovascular repair or bowel resection can be considered on a case-by-case basis before central repair^36,61.

Renal malperfusion can be diagnosed in patients with oliguria/anuria associated with increased serum creatinine levels⁸. Multiple causes may lead to renal malperfusion, some of which involve the renal artery by dissection; others occur secondary to hypoperfusion⁶⁷. In these results, renal malperfusion was present in 5% of reporting studies and was associated with a 21% in-hospital mortality rate. Several studies have reported that renal malperfusion is an independent predictor of operative mortality rate but is not associated with the long-term mortality rate (8-year follow-up) post-ATAAD surgery^41,67,68. Other studies reported an adverse outcome of an increased mortality rate at the 10-year follow-up in patients with an acute kidney injury postcardiothoracic surgery, including patients whose renal function fully recovered. Endovascular techniques (percutaneous aortic fenestration and renal artery stenting) in conjunction with early aortic repair can be used to restore renal blood flow in this patient group^34,68,69. Therefore, enhanced renal protection strategies and close clinical follow-up postdischarge may be necessary in this patient cohort^70,71.

In the present study, spinal malperfusion was present in 1% of the patient population and resulted in an in-hospital mortality rate of 18%. Spinal malperfusion can be diagnosed in patients with newly developed preoperative paraplegia and paraparesis that is not caused by lower leg ischaemia^38,44. The spinal cord injury symptoms will remain after surgery without a malperfusion-oriented strategy. Isolated spinal malperfusion necessitates urgent surgical repair of the proximal aorta in order to restore blood flow to the anterior spinal artery⁶. Persistent paraplegia postrepair may require cerebrospinal fluid drainage to increase the spinal perfusion pressure and improve blood flow^69,72. In elderly patients with a thrombosed false lumen of the ascending aorta, spinal drainage alone can be performed without central repair³⁸.

Although spinal cord malperfusion was found to have the lowest prevalence, it can result in significant disability, mortality rate and reduced quality of life in survivors. A study reported long-term survival at the 5-year follow-up to be 64.7% (versus 71.9% without spinal cord ischaemia)⁷³. Whilst neurological function following mild spinal cord ischaemia may be restored with rehabilitation, severe ischaemic injury can result in paraplegia⁷⁴. This can have a marked impact on the patient’s quality of life. A study assessing outcomes following spinal cord infarction at the 7-year follow-up reported that patients with spinal malperfusion had higher rates of employment and lower mortality rates, but higher rates of chronic pain and lowered functional independence, compared with cerebral malperfusion patients⁷⁴. After symptoms have been stabilized, rehabilitation should be commenced as soon as possible. Repetitive functional training is important to facilitate patients’ reintegration into their preoperative social circumstances⁷⁵. The collective efforts of the team can maximize the patient’s likelihood of regaining functional recovery.

This study offers a comprehensive assessment of the incidence of various malperfusion types in patients with ATAAD. These findings can assist surgeons in recognizing and managing common malperfusion issues early in diagnosis and treatment. The major limitation of this pooled analysis is that included studies did not specify whether organ malperfusion data was specific to a single organ or multiple organs. The present study also did not explore if the presence of one malperfusion can predict or correlate with another. Thus, while the results from this study suggest the trend of mortality rate in the presence of certain types of malperfusion, the results related to mortality rates should be interpreted cautiously. Whilst single-organ malperfusion data were included where possible, if non-specified data were reported in some studies involving more than one organ, it could contribute to reporting bias. In addition, the potential effects of revascularization strategies and the changing approaches in treating ATAAD^76,77 can impact the associated mortality rate. Lastly, the data on the impact of preoperative malperfusion on long-term outcomes (for example 1-year mortality rate) was not readily available for the complete data set and was not analysed.

Survival during hospital admission can vary depending on the presence and type of malperfusion, with mesenteric, coronary and cerebral malperfusion being associated with the highest in-hospital mortality rates. Organ-specific malperfusion syndromes should be considered when assessing the perioperative risk and surgical planning of patients undergoing surgical repair for ATAAD.

Funding

The authors have no funding to declare.

Disclosure

The authors declare no conflict of interest.

Supplementary material

Supplementary material is available at BJS Open online.

Data availablity

The data used in this meta-analysis is publicly available. The final data extraction sheet can be shared upon reasonable request from the corresponding author.

Author contributions

Ashwini Chandiramani (Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing—original draft), Mohammed Al-Tawil (Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft), Assem Elleithy (Data curation, Investigation, Methodology), Sahil Kakar (Data curation, Investigation, Methodology), Tharun Rajasekar (Data curation, Investigation, Methodology), Abinash Panda (Supervision, Validation), Haytham Sabry (Supervision, Validation), Assad Haneya (Supervision, Validation) and Amer Harky (Conceptualization, Supervision, Validation, Writing—review & editing)