Physiologic and management considerations for the patient

In the ICU, the newborn with CHD must be closely monitored with continuous invasive blood pressure, electrocardiograph, and pulse oximetry. COVID-19 status should be immediately evaluated from the maternal history, clinical manifestations, and laboratory and radiographic testing, when necessary.

The newborns affected by COVID-19 may be asymptomatic, mild, or severely affected. The clinical symptoms are non-specific and overlap with other infections, such as fever, temperature instability, respiratory symptoms, poor feeding, and abdominal distension. Although criteria for testing for COVID-19 may vary according to geographical regions, there are some guidelines provided by Centers for Disease Control and Prevention^34,35 and World Health Organisation.² Babies born to mothers with suspected or confirmed COVID-19, critically ill newborns needing ICU care with unexplained viral pneumonia or respiratory failure, and those having a history of close contact with patients with laboratory-confirmed COVID-19 within 14 days of symptom onset should be tested for COVID-19.

If possible, during this pandemic, it is advised to perform preoperative COVID-19 testing on every patient, even asymptomatic patients, as well as their parents.^{Reference Levy, Blumenthal and Chiotos36} The best test for SARS-CoV-2 in the peri-operative setting is a polymerase chain reaction of respiratory secretions. A positive serology will demonstrate prior exposure (or maternal status for neonates) rather than active illness, so is less useful in a peri-operative setting. Elective surgeries should be delayed until COVID-19 virus detection results are negative at least twice with a minimum of 24 hours between tests, since the first test may be false negative. The incubation period for COVID-19 is ranged between 4 and 6 days and may be as long as 14 days.^{Reference Huang, Wang and Li4} If the patient’s clinical condition is favourable, it is more prudent to delay the surgery until the patient’s symptoms have improved and/or testing has been repeated (often after 14 days) and is negative. For emergency procedures, COVID-19 status of the patient should be immediately evaluated.^{Reference Levy, Blumenthal and Chiotos36}

Symptomatic and supportive treatment is the mainstay of therapy including the supply of oxygen, the maintenance of water–electrolyte, and acid–base balance. The supplementation of water and electrolytes should be appropriate, to avoid aggravating the pulmonary oedema and reduced oxygenation, especially for newborns with CHD.

On 27 May, 2020, World Health Organisation recommended that the drugs including chloroquine and hydroxychloroquine (+/− azithromycin), antivirals, immunomodulators, and plasma therapy should not be administered as treatment or prophylaxis for COVID-19, outside of the context of clinical trials.³⁷ However, on 4 June, 2020, two studies of drug therapy (hydroxychloroquine and angiotensin-converting enzyme inhibitors) and COVID-19 have been retracted from two different journals, because a number of the authors were not granted access to the underlying data.^{Reference Ryan Syrek38} Since hydroxychloroquine may increase the risk of QTc prolongation, extreme care should be taken especially in patients with CHD.^{Reference Levy, Blumenthal and Chiotos36}Initial paediatric reports suggest that in the case of severe acute respiratory distress syndrome, high-dose pulmonary surfactant, inhaled nitric oxide, high-frequency oscillatory ventilation, and extracorporeal membrane oxygenation may be useful.^{Reference Kamali Aghdam, Jafari and Eftekhari11,Reference Chen, Guo and Wang29}

Workflow considerations for the healthcare team

During the current COVID-19 pandemic, healthcare authorities have advised delaying many elective procedures/surgeries to reduce the burden of the hospitals in adults. The preventive measures and treatment algorithms have been updated by authorities day by day in the light of experienced data on COVID-19. There is no specific guideline for CHD babies with COVID-19 in our country. It should be emphasised that delaying elective procedures is dependent on local/regional COVID-19 infections requiring hospitalisation, which in turn impacts resources available for the inpatient care of newborns with CHD. As surgeries in newborns with critical CHD need to be done in a timely fashion, it would be unethical to withhold life-saving cardiac surgery in a neonate in order to free up an ICU bed for an older adult with COVID-19. Therefore, decision of the time of surgery should ideally be given made by an experienced cardiac team.^{Reference Slidell, Kandel and Prachand39}

In the neonatal period, cardiac surgeries for CHDs with minimal risk of haemodynamic instability^{Reference Sanapo, Moon-Grady and Donofrio32,Reference Saxena, Relan and Agarwal40} such as ductal-dependent lesions, including hypoplastic left heart syndrome, critical coarctation, severe aortic stenosis, interrupted aortic arch, and pulmonary atresia, can be shortly delayed after starting prostaglandin E1 infusion. Currently, Stephens et al^{Reference Stephens, Dearani and Guleserian41} suggested guidance for surgical prioritisation in newborns with CHD for COVID-19 crisis management in CHD. In Table 1, we summarise recommendations on timing of surgery for common CHDs in neonatal period and early infancy during the COVID-19 pandemic.^{Reference Saxena, Relan and Agarwal40,Reference Stephens, Dearani and Guleserian41} It should be noted that although the newborns with ductal-dependent lesions can have surgery delayed for an extended period of time after starting prostaglandin E1 infusions, the longer these neonates are waiting for surgery, the more likely they are to develop complications, particularly those with ductal-dependent systemic blood flow (e.g., hypoplastic left heart syndrome). Furthermore, as the newborns receiving a prostaglandin E1 infusion are cared for in an ICU due to the risk of apnoea and other complications, delaying these neonatal CHD surgeries during the pandemic is likely to complicate the care of the patients.

Table 1. *Recommendations on timing of surgery for common CHDs in neonatal period and early infancy during the COVID-19 pandemic.^{Reference Saxena, Relan and Agarwal40,Reference Stephens, Dearani and Guleserian41}

AVSD: atrio-ventricular septal defect, AV Block: atrioventricular block, AS: aortic stenosis, BAS: balloon atrial septostomy, BAV: balloon valvuloplasty, HF: heart failure, HLHS: hypoplastic left heart syndrome, iVS: intact ventricular septum, PBF: pulmonary blood flow, PDA: patent ductus arteriosus, PGE1=prostaglandin-E1, PS: pulmonary stenosis, SBF: systemic blood flow, VSD: ventricular septal defect, TAPVR: total anomalous pulmonary venous return, TGA: transposition of great arteria, TOF: tetralogy of Fallot

* Note: Although the newborns with ductal-dependent lesions can have surgery delayed for an extended period of time after starting PGE1 infusions, the longer these neonates are waiting for surgery, the more likely they are to develop complications, particularly those with ductal-dependent systemic blood flow (e.g., HLHS)

The need for surgery for a newborn with CHD and suspicion of COVID-19 should be prioritised by an experienced neonatologist, infectious diseases specialist, paediatric cardiologist, and cardiovascular surgeon. Timing of surgery should be planned according to resource utilisation (anticipated ventilator duration, ICU stay, blood product usage),; clinical status of the patient; risk of delaying surgery; risk of exposure for the patient, family, and healthcare staff; co-morbidities; complexity of the procedure; and recommendations of professional societies.^{Reference Saxena, Relan and Agarwal40,Reference Stephens, Dearani and Guleserian41} Priority can be given to alternative approaches that may need less resources and/or result in shorter hospitalisation, e.g., a ductal stent opposed to a surgical systemic-to-pulmonary artery shunt.^{Reference Levy, Blumenthal and Chiotos36,Reference Stephens, Dearani and Guleserian41}

Aerosol-generating procedures should be performed with great caution in a negative pressure environment, if possible. Symptomatic infants who require intubation and/or positive pressure support in the ICU setting should ideally be admitted to negative pressure isolation rooms or single-patient rooms with closed doors. The air exiting a negative isolation room should be filtered with a high-efficiency particulate air filter to remove viruses and bacteria.

The American Society of Echocardiography stated that imaging should be performed according to local standards for the prevention of virus spread.^{Reference Barker, Lewin and Donofrio42} Tan et al^{Reference Tan and Aboulhosn27} released practical guidelines about potential resource allocation for congenital cardiac catheterisation. The authors recommended reducing case volumes of paediatric/congenital catheterisation laboratories during the pandemic.

The postponement of elective cases needs to be made at the individual centre level based on the number of total (paediatric and adult) COVID-19 patients requiring hospitalisation and ICU care, other resources (such as blood products availability), and preoperative testing capacity.

Currently, in our hospitals, emergency cardiac interventions/surgeries have been permitted to proceed. However, concerning preventive measures to reduce the spread of COVID-19, elective surgeries were largely postponed in “pandemic hospitals” or directed to the “non-pandemic hospitals” serving as cardiac centres for CHD. For critical cases, planning the intervention within the current cardiac centre is recommended, after having appropriate preventive measurements. This approach can reduce the risk of contamination that may occur during patient transport.

Mechanical ventilators, anaesthesia machines, monitors, transoesophageal echocardiography probes, ultrasound machines, perfusion pumps, blood gas analysers, activated-clotting time machines, and disposable supplies in the operating room should be prepared in advance. All the necessary items such as intubation items, peripheral arterial/central venous cannulation, syringes, gauze, surgical drapes, surgical instruments, sutures, cannulas for cardiopulmonary bypass, oxygenator and circuit for cardiopulmonary bypass, prosthetic grafts, and valves should be settled before the patient enters the operating room. The high-touch equipment such as anaesthesia workstation, infusion pumps, cardiopulmonary bypass machine, cell-saver device, and heat exchangers should be wrapped with plastic sheets to facilitate decontamination.^{Reference Mavioğlu, Ünal and Aşkın43}

Physiologic and management considerations for the patient

A newborn with or suspected of having COVID-19 should be transferred to the COVID-19 operating room under preventive measures in a separate transport incubator. The equipment used for transport should be disinfected at pre- and postoperative transportation of COVID-19 patients. During transport, the use of an in-line high-efficiency particulate air filter is recommended. The transportation of a COVID-19 patient from operating room to cardiac ICU should be performed by a personnel with protective equipment (i.e., gloves, gown, and eye protection, such as safety goggles) to protect medical staff from COVID-19.³⁵

Routine monitoring should be kept on in the operating room. Since the need for aerosolising procedures like intubation and transoesophageal echocardiography for surgery, all patients should be treated as confirmed COVID-19 cases when the disease is suspected or when the test result is not yet available.

Continued invasive haemodynamic monitoring is recommended to guide fluid therapy and the use of inotropic or vasoactive medications.

Protective mechanical ventilation strategy (target tidal volume 4–6 mL/kg peak inspiratory pressure ≤25 cm H₂O, to target SaO₂ about 88% to 95%, and pH ≥ 7.25) should be applied in suspected/confirmed COVID-19 patients. However, this approach would only apply to COVID-19 patients with significant parenchymal lung disease. Some of these ventilator strategies would be inappropriate for neonates with critical CHD, even if they had a COVID-19 infection, if significant lung disease was not present.

Since COVID-19 patients have a high incidence of acute kidney injury, peritoneal dialysis may be necessary in the postoperative period and the care team should consider the risks and benefits of peritoneal dialysis catheter placement at the time of surgery.^{Reference Stephens, Dearani and Guleserian41,Reference Chen, Liu and Gong44-Reference Wax and Christian46} Blood conservation strategies should be considered for COVID-19 patients because of the high risk of coagulation dysfunction. For all patients, coagulation status should be evaluated by platelet counts/function, prothrombin time, partial thromboplastin time, international normalised ratio, and thromboelastography. Antifibrinolytic medications, preoperative haemodilution, autologous platelet-rich plasma technology, mild hypothermia or normothermia during cardiopulmonary bypass, and intraoperative blood salvage should be used to reduce the risk of transfusion-related lung injury.^{Reference Stephens, Dearani and Guleserian41,Reference Wax and Michael47}

Intraoperative transoesophageal echocardiography is recommended to monitor ventricular function, volume status, and valvular diseases and guide the anaesthetic management. Right heart dysfunction might develop from increased pulmonary vascular resistance owing to pulmonary oedema, left heart dysfunction, and cardiomyopathy in COVID-19.^{Reference Wax and Christian46} There is a concern for transoesophageal echocardiography related to potential aerosolisation with coughing and gagging. However, this risk is negligible in an intubated neonate under general anaesthesia and so intraoperative transoesophageal echocardiography is not accepted as an aerosolising procedure. Lung ultrasonography may be useful to assess the severity of lung disease.^{Reference Smith, Hayward, Innes and Miller48}

The decision on whether to employ extracorporeal membrane oxygenation support for COVID-19-positive patients can be controversial and will depend on resource availability, co-morbidities, and pre-illness clinical status. Some experts have recommended that extracorporeal membrane oxygenation may be considered in a newborn with CHD who is positive and otherwise healthy prior to COVID infection.^{28,Reference Stephens, Dearani and Guleserian41}

Workflow considerations for the healthcare team

Most operating rooms are equipped with positive-pressure systems to ensure that air travels from operating rooms to adjacent areas, thus minimising inflow of air to the room. Negative pressure rooms may increase the risk for surgical site infection, and the recommendation to change them into negative pressure rooms is controversial.^{Reference Chow, Kwan and Lin49} COVID-19 crisis led to the construction of a negative pressure operating room in some hospitals. Although a dedicated negative pressure room is ideal for management of such patients to prevent airborne virus spreading to adjacent areas, this should be reserved for those confirmed to be infected. In our country, operating rooms of older hospitals generally have positive pressure environments. However, new city hospitals have included negative pressure operating rooms.

Hospitals should consult with their biomedical engineers to see if any operating rooms can be converted to negative pressure environments with airflow changes. A warning sign for COVID-19 should be posted outside the operating room. The feasibility of the operating room setup and a work-plan schedule is an important issue for all surgeries. Distribution of the surgical devices and anaesthetic equipment should be unique for the predefined COVID-19 operating room. All non-essential surgical and anaesthetic equipment should be taken out of the operating room. Coordination of the healthcare workers, the work-plan schedule of the COVID-19 operating room, and designated personnel working at the COVID-19 operating room should be planned day by day.

The work-plan schedule of the COVID-19 operating room should include routine universal infection prevention practices, donning and doffing personal protective equipment, and decontamination after the procedures. Table 2 shows the donning and doffing procedure for personal protective equipment according to the guidelines.^{35,Reference Li, Zeng and Li50}

Table 2. Donning and doffing procedure of personal protective equipment.^{35,Reference Li, Zeng and Li50}

A minimum number of personnel including the anaesthesiologist, anaesthesia technician, surgeons, nurse staff, and perfusionist should be assigned before the COVID-19 patient enters the operating room. Irrelevant staff should not enter the room to minimise the traffic across the operating room. Medical personnel should enter and exit the operating room in strict accordance with the principles of clean area, contaminated pollution area, and buffer zones.^{Reference Mavioğlu, Ünal and Aşkın43,Reference Li, Zeng and Li50} Figure 1 shows an algorithm aiming the protect surgical team members (surgeons, nurses, anaesthesiologist, technicians) in operating room in terms of emergency of surgery and COVID status of the patient.

Figure 1. Algorithm aiming the protect surgical team members (surgeons, nurses, anaesthesiologists, technicians) in the operating room. CHD: congenital heart disease, PCR: polymerase chain reaction, PPE: personal protective equipment: gown, gloves, and eye protection

The staff performing tracheal intubation should be covered by personal protective equipments. Correct donning and doffing of protective equipments are essential for avoiding transmission and should be performed with a trained member of staff following local guidelines. Before intubation, avoidance of bag mask ventilation is not universally recommended as it is deemed low aerosolisation risk. Furthermore, avoidance of bag mask ventilation in neonates before laryngoscopy is very difficult in the presence of CHD. It is important that the patient coughing during laryngoscopy should be avoided with the use of adequate muscle relaxation prior to laryngoscopy. Following the intubation, ventilator is connected to the patient, before positive pressure ventilation is started. The ventilatory circuit should not be disconnected unless needed.^{Reference Wax and Christian46} The use of closed suction system (The Ballard® Trach Care™) designed to safely suction neonatal and children on mechanical ventilation provide protection for both the patient and the caregiver. The use of high-efficiency particulate air filters between the Ballard and the anaesthesia machine is recommended to reduce the risk of cross-infections and to prevent the contamination of the machine.^{Reference Wax and Christian46,Reference Wax and Michael47} Arterial and central venous catheterisations are recommended to be performed under ultrasound guidance to improve success rate and reduce procedure time.

For cardiac anaesthesia, sevoflurane is an agent of choice for inhalation induction. Propofol or ketamine is used for intravenous induction. The likely physiological consequences of varying systemic and pulmonary vascular resistances on shunts and cardiac output must be considered in selection of anaesthetic agents. The depth of anaesthesia should be adjusted to avoid hypotension and the need for inotropic drugs.^{Reference Wax and Christian46,Reference Wax and Michael47}

After the surgery, all the surgical gowns and gloves must be taken off at the COVID-19 operating room at an allocated place for doffing. All medical waste, including breathing tubes, infusion tubing, and disposable laryngoscopes, must be sealed with double-layered medical waste bags and treated as infectious medical waste. The anaesthesia workstation should be properly sterilised according to the manufacturer recommendations.^{Reference Mavioğlu, Ünal and Aşkın43,Reference Wax and Christian46,Reference Wax and Michael47}

SARS-CoV-2 is known to be sensitive to ultraviolet rays and heat. Coronaviruses can be inactivated by lipid solvents, including either (75%), ethanol, chlorine-containing disinfectant, peroxyacetic acid, and chloroform except for chlorhexidine. Therefore, chlorine containing disinfectants are accepted to be appropriate to clean the operating room floor and wipe the surface of reusable medical equipments. Cleaning should be delayed until the air in the room is turned over several times according to the recommendations of biomedical engineering department based on the air handling system. Ultraviolet light decontamination for the room is recommended prior to use for a COVID-negative or unknown patient.^{Reference Mavioğlu, Ünal and Aşkın43,Reference Wax and Christian46,Reference Wax and Michael47}

For healthcare providers, at least 14 days of quarantine is recommended if exposure to COVID-19 occurs with inadequate personal protective equipment during care.^2,34

Physiologic and management considerations for the patient

The patients should be transferred to ICU under preventive measurements as previously mentioned. Neonates undergoing cardiac surgery, with or without the use of extracorporeal circulation, as per protocol are rarely extubated in the operating room. During transport of the patients, ventilation should be performed by a disposable ambu bag or transport ventilator. The use of an in-line high-efficiency particulate air filter is recommended. The positive pressure ventilation should be stopped before disconnection from the ventilator, while placing the patient on the ambu bag. Non-invasive ventilation (e.g., Continuous Positive Airway Pressure or Bilevel Positive Airway Pressure) should be avoided as it may increase the risk of infectious transmission in patients with COVID-19 and should never be used outside of appropriate airborne/droplet isolation.^{Reference Chen, Liu and Gong44,Reference Wax and Christian46,Reference Wax and Michael47}

The potential effects of COVID-19 on myocardial injury during cardiac surgery with cardiopulmonary bypass

Anaesthesia and major surgery can produce immune-inflammatory responses in patients with CHD. Systemic inflammatory response syndrome is frequently observed in children after open-heart surgery.^{Reference Durandy51} Newborns, especially with lower birthweights, are reported to be more vulnerable to develop systemic inflammatory response syndrome following cardiopulmonary bypass. Systemic inflammatory response syndrome can impair the function of the heart, lung, kidney, liver, brain, and intestine. In a COVID-19-positive neonate, an approach that avoids the deleterious effects of cardiopulmonary bypass (i.e., pulmonary artery banding, hybrid procedure, balloon angioplasty, or valvuloplasty, etc.) may be more prudent.^{Reference Levy, Blumenthal and Chiotos36,Reference Stephens, Dearani and Guleserian41}

Available evidence suggests that excessive inflammation, oxidation, and an exaggerated immune response play important role in the pathogenesis of COVID-19. These events cause a cytokine storm and further progression to acute respiratory distress syndrome. The immune function of the patient has a major impact on the disease severity, and populations with low immune function, such as newborns, can be more susceptible.

In a recent report, it was suggested that surgery might accelerate and exacerbate the disease progression of COVID-19. Direct myocardial injury mediated via angiotensin-converting enzyme-2, viral pneumonia, acute respiratory distress syndrome, acute lung injury, hypoxia-induced myocardial damage, cardiopulmonary bypass -related systemic inflammatory response syndrome, pulmonary oedema/hypertension associated to CHD may contribute to inflammation process resulting in heart failure. Figure 2 shows possible mechanisms of myocardial injury in a newborn patient with COVID-19, undergoing cardiopulmonary bypass due to truncus arteriosus.

Figure 2. Possible mechanisms of myocardial injury in a newborn patient with COVID-19, undergoing cardiopulmonary bypass due to truncus arteriosus. CPB: cardiopulmonary bypass, ACE: angiotensin-converting enzyme, ARDS: acute respiratory distress syndrome, SIRS: systemic inflammatory response syndrome

During cardiac surgery with cardiopulmonary bypass, accelerated inflammatory response may be reduced by off-pump cardiac surgery, control of temperature (32 to 34°C for operations <2 h of cardiopulmonary bypass), heparin coated-perfusion circuits, modified ultrafiltration, and glucocorticoids. Performing minimally invasive extracorporeal circulation and utilising the cell-saver device may both have preventive effects on the immune response, reducing the systemic cytokine load. These strategies should be kept in mind for COVID-19 patients during open cardiac surgery.

In the ICU, the COVID-19 patients should be closely monitored for systemic inflammatory response syndrome and respiratory complications and multiorgan failure. As a usual procedure, the thymus gland is routinely removed to eliminate the risk of compression on the heart and great vessels during cardiac surgery requiring a midline incision. The thymus is known to be the site of T cell development in human. However, there is no evidence that this constitutes an additional risk for infection.²⁸

Anticoagulants are frequently used in cardiac surgeries. Coagulation dysfunction may develop in the course of COVID-19 infection. Therefore, modification of perioperative anticoagulation approaches (use of low-dose heparin infusions, enoxaparin use, etc.) may be considered in these patients.^{Reference Chen, Liu and Gong44}

COVID-19 may cause acute renal injury and multiorgan failure. Since newborns also have higher levels of renal failure post-cardiopulmonary bypass, strict monitoring of fluid/nutritional intake is recommended to guide fluid therapy.^{Reference Stephens, Dearani and Guleserian41,Reference Guvener, Korun and Demirturk52}

In general, the use of corticosteroids is not recommended as it may prolong viral replication in patients with COVID-19.^{Reference Levy, Blumenthal and Chiotos36} However, many neonates receive steroids to attenuate the inflammatory response to cardiopulmonary bypass during surgery. Therefore, steroid use should be evaluated on a patient basis considering the risk-to-benefit ratio.

In addition to supportive care, the indication of antiviral treatment should be consulted with the neonatologist and infectious diseases specialist, by the updated guideline recommendations. There may be a role for convalescent plasma (plasma from patients who have had COVID19 and now have antibodies) during neonatal critical illness.^{Reference Levy, Blumenthal and Chiotos36}

The newborn patients born to mother with COVID-19 can be fed with breastmilk (bottle or nasogastric tube) by an uninfected caregiver.^{2,Reference Amatya, Corr and Gandhi14,53}

During the SARS-CoV-2 pandemic, for the health and safety of the patients, parental visiting should be limited. Of course, visitor restrictions may vary at different centres depending on local and regional COVID-19 infection rates in the community. All visitors and caregivers must wear a mask at all times.^2,34,35

Workflow considerations for the healthcare team

The number and the shift of the healthcare workers should be arranged according to the conditions of the healthcare facilities. COVID-19 newborn patients should be followed up by a dedicated cardiac COVID-19 team including an anaesthesiologist, cardiovascular surgeon, paediatric cardiologist, neonatologist, and infectious diseases specialist. The multidisciplinary approach can reduce expert bias for postoperative care. In this digital age, it may be considered as an option to perform the visits and consultations more widely by using applications such as video call telemedicine instead of in-person routine visits to prevent possible nosocomial COVID-19.