Vasoplegic syndrome in patients undergoing heart transplantation

Objectives To summarize the risk factors, onset time, and treatment of vasoplegic syndrome in patients undergoing heart transplantation. Methods The PubMed, OVID, CNKI, VIP, and WANFANG databases were searched using the terms “vasoplegic syndrome,” “vasoplegia,” “vasodilatory shock,” and “heart transplant*,” to identify eligible studies. Data on patient characteristics, vasoplegic syndrome manifestation, perioperative management, and clinical outcomes were extracted and analyzed. Results Nine studies enrolling 12 patients (aged from 7 to 69 years) were included. Nine (75%) patients had nonischemic cardiomyopathy, and three (25%) patients had ischemic cardiomyopathy. The onset time of vasoplegic syndrome varied from intraoperatively to 2 weeks postoperatively. Nine (75%) patients developed various complications. All patients were insensitive to vasoactive agents. Conclusions Vasoplegic syndrome can occur at any time during the perioperative period of heart tranplantation, especially after the discontinuation of bypass. Methylene blue, angiotensin II, ascorbic acid, and hydroxocobalamin have been used to treat refractory vasoplegic syndrome.


Introduction
Vasoplegic syndrome (VS) is a common life-threatening complication characterized by severe and persistent systemic arterial hypotension (mean arterial pressure, <50 mmHg), normal or slightly increased cardiac output (cardiac index, >2.5 L/min/m 2 ), low systemic vascular resistance (SVR, <800 dyne/s/cm 5 ), and insensitivity to appropriate fluid resuscitation and high-dose vasopressors (1). VS occurs in up to 34.8% of patients who undergo heart transplantation (HTX) (2). The incidence of VS is higher in patients who underwent HTX compared to other forms of cardiac surgery, e.g., off-pump coronary artery bypass graft (CABG) (2.8%) (3), on-pump CABG (6.9%-26%) (3,4), and aortic valve replacement (AVR) (20%) (5). Earlier research (6) showed that the incidence of VS is as high as 45% in patients with a ventricular assist device (VAD) at the time of HTX. Chemmalakuzhy et al. (7) observed increased risk for early mortality among HTX recipients with VS, with a 30-day mortality rate of 33%. This study aimed to summarize the risk factors, onset time, and treatment of VS in patients undergoing HTX.

Search strategy
Relevant case reports were searched using the PubMed and OVID electronic databases from inception until January 14, 2022. Chinese literatures from the CNKI, VIP, and WANFANG databases were also searched. Different combinations of terms that included "vasoplegic syndrome," "vasoplegia," "vasodilatory shock," and "heart transplant*" were used in the search strategy. All relevant case reports were included. The exclusion criteria were as follows: (a) non-English and non-Chinese studies; (b) studies based on animal models; and (c) duplicate publications. Each author independently read the titles and abstracts of all the identified reports for eligibility, excluding ineligible reports. The eligibility of the remaining reports for final inclusion was determined by examining the full-text versions of the publications.

Data abstraction
Data of interest from the included case reports were abstracted and tabulated by each author independently: (a) author, year, and journal of publication; (b) total number of patients, age, sex, medical history, number of thoracotomy surgeries, bleeding and coagulopathy or not, postoperative transesophageal echocardiography, treatment of ventricular dysfunction (VD), and complications; (c) onset time, clinical manifestation, and treatment of VS. Disagreements were resolved by discussion between both authors during the process of data abstraction.
The time to onset of VS ranged from during CPB to 2 weeks postoperatively; nine (75%) patients experienced VS intraoperatively, and three (25%) patients experienced VS postoperatively ( Figure 2). All patients were insensitive to vasoactive agents, developed persistent hypotension, and were subsequently administered methylene blue (MB), hydroxocobalamin, ascorbic acid (AA), and ANG-II.

Discussion
Several risk factors for VS have been identified, including ACEI, βblockers, calcium channel blockers, heparin, amiodarone, diabetes mellitus, prolonged CPB, congestive heart failure, and left ventricular ejection fraction <35% (17,18). The preoperative use of VAD in adults is an independent risk factor for VS (6). In this study, six (50%) (11,13,15,16) patients had used LVAD before surgery. Of the 12 patients, 8 patients (10, 11, 13, 15, 16) had undergone previous thoracotomy. This easily led to dense adhesions between the mediastinum and pericardium, resulting in severe bleeding and coagulation disorders, requiring a large number of blood products and factor replacement. Administration of blood products activates pro-inflammatory mediators during surgery (18). Packed red blood cells, fresh frozen plasma, and platelet transfusion increase the prevalence of VS (19). In addition, packed red blood cell transfusion exhibited a dose-dependent increase in the development of VS with each packed red blood cell unit transfused (19).
Milrinone is a powerful inotropic agent commonly used for right ventricular dysfunction, and may exacerbate systemic vasoplegia (20). Of the 12 patients, 8 (9, 12-14, 16) used milrinone pre-or intraoperatively. A meta-analysis (21) revealed that 38% of patients with New York Heart Association class III heart failure symptoms and 42% of those with class IV symptoms experienced depression. Depression not only increases the incidence of hypertension, coronary heart disease, and diabetes, but also causes chronic inflammation (22,23). The mechanism of VS is largely unknown, and study results suggest that VS is correlated with the release of cytokines, such as tumor necrosis factor (TNF) and interleukin-1, which increase nitric oxide (NO) production, resulting in marked relaxation of the vascular smooth muscles (24). Therefore, the chronic inflammatory state of patients before surgery may be a risk factor for VS. Other chronic inflammation diseases include obesity, obstructive sleep apnea, chronic kidney disease, and smoke (25-28). Eight (67%) patients (9, [11][12][13]15) had at least one of these medical histories. The risk factors for VS in the patients undergoing HTX are summarized in Table 2.
Of the 12 patients, 9 (75%) experienced VS intraoperatively, including 4 patients before weaning from CPB and five after discontinuation of CPB. The other three patients had VS after arriving at the intensive care unit, and one developed VS 2 weeks postoperatively. Septic shock is considered more likely than VS 2 weeks after surgery. Therefore, the possibility of infection must be ruled out, especially infections of the chest, abdomen, genitourinary system, and bloodstream, which account for >80% of sepsis cases (29)(30)(31).
When VS occurs, catecholamines and vasopressin should be used at first. However, high-dose catecholamines may lead to tissue hypoperfusion and myocardial ischemia. Furthermore, prolonged hypotension may have adverse consequences, such as gradual deterioration of ventricular function and decreased urine output. At present, four drugs are used to treat refractory VS ( Table 3). MB and hydroxocobalamin increase SVR by inhibiting NO synthase and reducing NO production, inhibiting the activation of soluble guanylyl cyclase, and binding to NO directly (32-35). Of the 12 patients, four were treated with at least two of these drugs. The combination of MB and hydroxocobalamin may be more beneficial than that of MB alone (36,37). One study (38) found that MB reduced the duration of VS and mortality. However, a potentially lethal complication of MB is serotonin syndrome, especially in patients taking serotonergic antidepressants. Fentanyl is the most commonly used narcotic analgesics, which reduces serotonin reabsorption; therefore, it should be used cautiously when fentanyl was used during surgery. Hydroxocobalamin, an injectable form of vitamin B12, interferes with dialysis treatment Flow diagram of study selection. owing to an alarm of blood leak, which can be overcome by continuous renal replacement therapy (39). AA is an essential cofactor for the endogenous biosynthesis of catecholamines, which cannot be synthesized by humans, and the concentration of AA in patients undergoing cardiac surgery after CPB is low (40)(41)(42). One study (43) found that the utilization of vasopressors was reduced when high-dose AA was administered for the treatment of VS after CPB. However, it should be noted that MB and AA cannot be used in patients with glucose-6-phosphate dehydrogenase deficiency to avoid hemolytic anemia. Prolonged exposure to CPB impairs the pulmonary capillary endothelium, thereby limiting the activity of angiotensin-converting enzyme (44). ANG-II acts directly on blood vessel walls, resulting in vasoconstriction, increased mean arterial pressure antidiuretic hormone secretion, adrenal cortex stimulation, and increased water reabsorption (44,45). The adverse effects of ANG-II include thromboembolic events, hypoperfusion from vasoconstrictive actions, and increased pulmonary vascular resistance (46,47). VS treatment of during the perioperative period of HTX is shown in Figure 3.
In addition to the abovementioned four drugs, induced mild hypothermia may be a useful treatment for VS. Earlier studies (48) showed that hypothermia decreases the release of cytokines. Furthermore, mild hypothermia effectively restored SVR and blood pressure within 4 h without adverse effects on pulmonary pressure (49), and improved the response to epinephrine (50) and norepinephrine (51). Therefore, it may be an excellent prevention and treatment method for VS by avoiding active rewarming after the operation and letting the patient gradually and spontaneously Onset time of vasoplegic syndrome. ICU, intensive care unit; CPB, cardiopulmonary bypass.   reach normothermia or maintain a 33°C-35°C corporeal temperature for the first 24 h after HTX. However, hypothermia can induce problems, such as cardiac arrhythmia and coagulopathy. Further research is necessary to determine the safety of mild hypothermia for the treatment of VS. In-hospital mortality was more than 2.5-fold higher in patients with (25%) than in patients without VS (52). Therefore, the prevention of VS is crucial for patients undergoing HTX. Ozal et al. (4) reported that those who received preoperative MB had significantly higher postoperative SVR and MAP, and a significantly shorter mean length of stay in intensive care units. A randomized, double-blind, controlled trial showed that tranexamic acid attenuates the development of VS after CPB by blocking fibrinolysis (53). Further research should prioritize the mechanism and prevention measures for VS in patients undergoing HTX.
In summary, several risk factors for VS exist in patients undergoing HTX, including the chronic inflammatory exhibited by some patients before surgery. VS can occur at any time during the perioperative period in patients who underwent HTX, especially after the discontinuation of bypass. MB, ANG-II, hydroxocobalamin, and AA have been used to treat refractory VS.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author.