bubble_chart Overview

Acute radiation disease is a systemic illness caused by the body being exposed to a large dose (>1Gy) of ionizing radiation in a short period of time. Both external and internal irradiation can lead to acute radiation disease, but external irradiation is the primary cause. The types of radiation that can cause acute radiation disease through external exposure include gamma rays, neutrons, and X-rays.

bubble_chart Etiology

Hematopoietic injury is a characteristic feature of bone marrow-type radiation sickness, which persists throughout the entire course of the disease. Within hours after irradiation, a decrease in the mitotic index of bone marrow cells is observed, along with sinus dilation and congestion. This is followed by necrosis of bone marrow cells, a reduction in hematopoietic cells, sinus hemorrhage and rupture, and bleeding. The decrease in blood cells occurs earlier in the erythroid series than in the granulocytic series, initially affecting immature cells and later mature cells as well. The extent of bone marrow changes is related to the irradiation dose. With a lower dose, the reduction in blood cells is only mild, and hemorrhage is not significant. With a higher dose, hematopoietic cells are severely depleted or even completely absent, leaving only residual fat cells, reticular cells, and plasma cells. Lymphocytes may show a relative increase, while other cells such as tissue basophils, osteoclasts, and osteoblasts also increase. Severe hemorrhage occurs, manifesting as significant bone marrow suppression. If sufficient hematopoietic stem cells remain after bone marrow destruction, hematopoiesis can still be reconstructed. Recovery of bone marrow hematopoiesis may begin in the third week after irradiation, with significant regeneration occurring 4–5 weeks post-irradiation. However, if the irradiation dose is extremely high, hematopoietic function often cannot recover on its own.

The changes in lymphocytes (primarily in the spleen and lymph nodes) follow a pattern similar to that of the bone marrow, characterized mainly by mitotic inhibition, cell necrosis, reduction, and hemorrhage. These changes progress faster than in the bone marrow and recover earlier, but complete recovery requires a longer time.

As the lesions in hematopoietic organs progress, the clinical course of bone marrow-type radiation sickness exhibits distinct stages, which can be divided into the initial stage [first stage], the latent period, the critical phase, and the stage of convalescence. This staging is particularly evident in moderate and grade III cases.

bubble_chart Clinical Manifestations

Hematopoietic injury is a characteristic of bone marrow-type radiation sickness, which persists throughout the entire course of the disease. Within hours after irradiation, a decrease in the mitotic index of bone marrow cells is observed, along with dilation and congestion of sinusoids. This is followed by necrosis of bone marrow cells, reduction of hematopoietic cells, sinusoid leakage, rupture, and hemorrhage. The decrease in blood cells occurs earlier in the erythroid lineage than in the granulocytic lineage, initially affecting immature cells and later mature cells as well. The extent of bone marrow changes is related to the irradiation dose. With a smaller dose, the reduction in blood cells is only mild, and hemorrhage is not significant. With a larger dose, hematopoietic cells are severely depleted or even completely absent, leaving only residual adipocytes, reticular cells, and plasma cells. Lymphocytes may relatively increase, while other cells such as tissue basophils, osteoclasts, and osteoblasts also proliferate, accompanied by severe hemorrhage, manifesting as severe bone marrow suppression. If sufficient hematopoietic stem cells remain after bone marrow destruction, hematopoiesis can still be reconstructed. Recovery of bone marrow hematopoiesis may begin in the third week post-irradiation, with significant regeneration occurring 4–5 weeks after irradiation. However, if the irradiation dose is very large, hematopoietic function often cannot recover on its own.

The pattern of changes in lymphocytes (primarily in the spleen and lymph nodes) is similar to that in the bone marrow, also characterized by mitotic inhibition, cell necrosis, reduction, and hemorrhage. However, these changes progress faster than in the bone marrow and recover earlier, though complete recovery requires a longer time.

As the lesions in hematopoietic organs progress, the clinical course of bone marrow-type radiation sickness exhibits distinct stages, which can be divided into the initial stage [first stage], latent period, critical phase, and stage of convalescence. This staging is particularly evident in moderate and grade III cases.

bubble_chart Diagnosis

The diagnosis of radiation sickness must determine whether the patient has acute radiation sickness, as well as assess the severity of the condition early and identify the stage of the disease at the time of diagnosis. This is crucial for guiding timely and effective treatment measures.

1. Early Classification
   Early classification should be conducted immediately after injury. In wartime, it begins at early treatment facilities, while in peacetime, it can be performed during the initial stage [first stage] of hospitalization. The primary basis for early classification is as follows:

   (1) Medical History
   This mainly refers to the exposure history. In wartime, based on the yield of the nuclear explosion, the method of detonation, the patient's location, and whether there was protection, an initial estimate of the patient's dose is made. If the exposure occurred outside a contaminated area, the dose is estimated based on the ground exposure rate in the contaminated area and the time the patient spent passing through or staying there. Additionally, it is important to determine whether the patient might have internal contamination.

   For peacetime accidental exposure, the potential dose is initially estimated based on the nature of the accident, the type and activity of the radiation source, the patient's location and duration of exposure, as well as the individual's movements during exposure and the presence of shielding.

   Whether in wartime or peacetime, if the patient is wearing a personal dosimeter, the reading indicated by the dosimeter should be promptly reviewed.

   (2) Initial Stage [First Stage] Symptoms
   The initial stage [first stage] symptoms exhibited by the patient within 1-2 days after exposure are valuable for assessing the condition.

   1. If nausea and loss of appetite occur in the initial stage [first stage] after exposure, the dose may exceed 1Gy; vomiting suggests a dose likely greater than 2Gy. Multiple episodes of vomiting may indicate a dose exceeding 4Gy. If vomiting and diarrhea occur very early, the dose may exceed 6Gy.
   2. If multiple episodes of vomiting occur within hours of exposure, accompanied by severe diarrhea but no neurological symptoms, intestinal radiation sickness should be considered.
   3. Frequent vomiting within the first hour of exposure, disorientation, ataxia, limb tremors, and increased muscle tone may strongly suggest cerebral radiation sickness. The occurrence of spasms, excluding trauma, confirms cerebral radiation sickness.
   A comprehensive analysis of initial stage [first stage] symptoms is essential, and psychological factors should be ruled out.
   (3) Laboratory Tests
   1. Absolute Lymphocyte Count in Peripheral Blood
      The rate of decline in the absolute lymphocyte count in peripheral blood early on is a good indicator of the severity of the condition, especially in wartime, as it is a simple and practical early test.
   2. Reticulocytes
      Changes in peripheral red blood cells occur later, but reticulocyte changes appear early. A significant drop in reticulocytes within 5 days of exposure corresponds to a dose of 3Gy or more. Their disappearance within 48 hours suggests a lethal dose.
   3. Hemoglobin Levels
      In the early stages of bone marrow radiation sickness, hemoglobin levels show little change, whereas in intestinal radiation sickness, they rise early.
2. Clinical Diagnosis
   Clinical diagnosis is a continuation of early classification and is inseparable from it. The goal is to complete the final definitive diagnosis based on the exposure dose, the progression of the condition, and various laboratory indicators.

(1) Physical and Biological Dose Measurement
Accurate measurement of the patient's exposure dose is the primary basis for assessing the condition. When possible, both physical and biological doses should be measured, as they complement each other to yield a more accurate value.

1. Physical Dose Measurement
   To gain a detailed understanding of the radiation field during the accident, the geometric positions of individuals relative to the radiation source, the presence of shielding, as well as the movement and time variations of personnel, etc. If the patient was wearing a personal dosimeter at the time, the position of the dosimeter should be noted. Collect items such as the patient's watch ruby and certain medications they carried; the former can be measured for radiation dose using thermoluminescence, while the latter can be assessed via electron spin resonance spectroscopy. In cases of neutron exposure, collect metal items carried by the patient, as well as biological samples such as hair, urine, and blood for neutron activation measurements to determine the neutron dose received. If necessary, conduct whole-body 24Na activation measurements and perform simulated irradiation measurements using human models. Subsequently, analyze and calculate the data to draw conclusions.
2. Biological dose measurement
   The use of certain sensitive radiation biological effect indicators in the body to reflect the dose received by a patient is called biological dose measurement. Currently, it is widely recognized that the lymphocyte chromosome aberration rate is an appropriate biological dosimeter, as it has a functional relationship with the radiation dose, especially suitable for the dose range of 0.25–5 Gy. However, the measurement method is relatively complex and needs to be performed in a specialized laboratory. The types of aberrations typically used for biological dose measurement are fragments, dicentrics, and centric rings. The method involves collecting blood within 24 hours post-irradiation (no later than 6–8 weeks), culturing it in vitro for 48–72 hours, and then observing the lymphocyte chromosome aberration rate.

Recently, some researchers have used the measurement of lymphocyte micronucleus frequency as a method for biological dose measurement. Lymphocyte micronuclei are small, round or oval bodies free in the cytoplasm, with a structure and staining similar to the main nucleus but smaller than one-third of its size. They may originate from chromosomal fragments. The measurement method is similar to that for chromosome aberration rate, but the observation and analysis are easier. Within the dose range of 0.2–5 Gy, the micronucleus frequency shows a linear relationship with the dose.

bubble_chart Treatment Measures

1. Treatment of Bone Marrow Radiation Sickness

   (1) Treatment Principles

   1. Comprehensive treatment centered on hematopoietic injury
      The primary issue in bone marrow radiation sickness is hematopoietic tissue injury. Therefore, the focus should be on mitigating and delaying the progression of hematopoietic organ injury while promoting recovery. Concurrently, vigorous efforts must be made to prevent complications such as infection and hemorrhage caused by hematopoietic injury. Additionally, since radiation sickness affects the entire body, comprehensive treatment remains essential to maintain internal balance and safely navigate the critical phase.
   2. Graded and Phased Treatment
      The treatment measures for different grades of radiation sickness are fundamentally similar but vary in complexity. Grade I radiation sickness in peacetime may require short-term hospitalization for observation and symptomatic treatment, while in wartime, symptomatic management and on-site observation may suffice. Grade II and above require hospitalization. However, early treatment for Grade II can be simplified, whereas Grade III and severe Grade III cases demand immediate hospitalization and proactive preventive measures. The principle of "emphasizing early intervention, targeting hematopoietic recovery, and focusing on the critical phase" helps improve cure rates. Treatment must also address the specific challenges of each phase.
   (1) Initial Stage: Symptomatic treatment is the priority, along with measures to mitigate injury based on disease characteristics.
   (1) Ensure the patient rests quietly and remains emotionally stable. (2) Administer anti-radiation drugs early. (3) Provide symptomatic treatment such as sedation and antiemetics (e.g., diazepam, metoclopramide). (4) For symptoms like conjunctival congestion or skin flushing, administer antihistamines (e.g., diphenhydramine, promethazine). (5) Improve microcirculation. (6) For Grade III and above, administer intestinal sterilization drugs early and implement strict isolation measures. (7) For severe Grade III cases, perform hematopoietic stem cell transplantation early.

   (2) Latent Phase: Focus on protecting hematopoietic function and preventing infection and hemorrhage.
   (1) Enhance nursing care, monitor disease progression, and encourage high-calorie, high-protein, high-vitamin, and easily digestible food intake. Severe Grade III patients may require intravenous nutrition via a retained catheter. (2) Protect hematopoietic function and delay or reduce injury (e.g., oral multivitamins, blood transfusions for Grade III). (3) Prevent infection and hemorrhage. (4) For severe Grade III patients requiring hematopoietic stem cell transplantation, proceed as early as possible if not done in the initial stage.

   (3) Critical Phase: Anti-infection and anti-hemorrhage measures are paramount, alongside strong supportive care, adequate nutrition, electrolyte balance, acidosis correction, and hematopoietic recovery.
   (1) Ensure absolute bed rest, control IV fluid rates to prevent pulmonary edema, and monitor disease progression. (2) Implement anti-infection and anti-hemorrhage measures. (3) Promote hematopoietic recovery with Vitamins B4, B6, B12, folic acid, DNA preparations, hematopoietic factors, and Chinese medicinals that tonify and harmonize qi and blood. (4) Provide adequate nutrition (including IV supplementation), supplement potassium and alkaline drugs as needed, and administer energy boosters like coenzyme A and ATP.

   (4) Convalescent Stage: Prevent relapse and address residual conditions.
   (1) Strengthen nursing care, avoid overexertion, prevent common colds and reinfection, monitor nutrition, and watch for complications. (2) Continue promoting hematopoietic recovery (e.g., iron supplements, tonifying Chinese medicinals, or small blood transfusions for anemia). (3) Address symptoms like indigestion symptomatically. (4) After clinical recovery, patients should rest and recuperate further, avoiding radiation work. After medical evaluation, they may resume appropriate duties.

   (2) Main Treatment Measures

   1. Early administration of anti-radiation drugs
      Anti-radiation drugs refer to a class of medications that can alleviate radiation sickness when administered either before irradiation or in the early stages after irradiation. They are particularly effective for moderate to grade III radiation sickness.
   2. Improvement of Microcirculation
      Early microcirculatory disturbances after irradiation can exacerbate tissue cell injury, particularly in cases of radiation sickness above grade III. Intravenous infusion of low-molecular-weight dextran, 500–1000 ml daily, supplemented with an appropriate amount of dexamethasone and compound Salvia miltiorrhiza injection, during the first three days post-irradiation can help improve microcirculation, increase tissue blood flow, and mitigate tissue injury.
   3. Prevention and Treatment of Infection
      Preventing and treating infections play a crucial role in therapy, especially during the critical phase, where infection control should be prioritized.
      (1) Admission Cleaning: Bathe or use a
      1. 5000 chlorhexidine medicated bath.
      (2) Disinfection and Isolation: During wartime, implement zonal isolation—separate rooms or wards from other injured or sick personnel to prevent cross-infection. Wards should be regularly disinfected with ultraviolet light and disinfectant solutions. In peacetime, patients above grade III should be admitted to laminar flow clean rooms.
      (3) Maintain Skin and Mucous Membrane Hygiene: Frequent bathing or sponge baths. Enhance oral care; toothbrushes are prohibited. Regularly rinse with disinfectant solutions. After each meal, rinse the mouth with disinfectant and wipe the oral cavity with cotton balls soaked in disinfectant. Perform medicated baths for the genitals and anus daily.
      (4) Use Intestinal Sterilizing Agents: For patients above grade III, administer oral intestinal bactericides early to reduce intestinal infections. Options include Coptis Rhizome extract, compound co-trimoxazole, neomycin, and gentamicin. Since intestinal bacteria are suppressed, supplement appropriately with Vitamins B4 and B2.
      (5) Systemic Antibiotic Use: A key measure for infection control, preferably used prophylactically when indicated. Indications include: (1) skin or mucous membrane hemorrhage, (2) presence of infection foci, (3) significantly accelerated erythrocyte sedimentation rate, (4) white blood cell count below 3×10⁹/L, (5) noticeable hair loss. Administer antibiotics if any one of these signs appears. Drug sequence may include sulfonamides, penicillin, streptomycin, ampicillin, methicillin, gentamicin, kanamycin, tobramycin, and cephalosporins. Use high doses, primarily via intravenous administration. Adjust drug types promptly based on blood or throat swab cultures and bacterial sensitivity tests, ensuring combination therapy and monitoring for adverse effects.
      (6) Enhance Immune Function: For grade II and mild grade III patients whose immune function remains intact, active immunization measures such as Corynebacterium parvum vaccine, BCG, or certain plant polysaccharides may be used to stimulate immune responses. For severe grade III and above patients, passive immunization is preferable, such as intravenous high-dose human gamma globulin or placental globulin.
      (7) Monitor and Treat Local Infections: Timely identify and rigorously manage potential infection foci, such as dental caries, stomatitis, skin boils, hemorrhoids, tinea pedis with erosion, or newly developed radiation-induced skin and mucous membrane injuries, to minimize infection risks.
      (8) Prevent and Treat Secondary Infections: For fungal infections, use antifungal agents like oral nystatin, aerosol inhalation, or gargles. Newer antifungals like ketoconazole tablets may also be administered. For viral infections, use acyclovir and ganciclovir.
      (9) Interstitial Pneumonitis Prevention and Treatment: Focus on improving respiratory function and preventing heart failure through oxygen therapy or assisted ventilation. Adrenocortical hormones can alleviate dyspnea and control symptoms. High-dose gamma globulin, antiviral drugs, and anti-cytomegalovirus serum are effective against viral infections.
   4. Prevention and Treatment of Hemorrhage
      The primary cause of hemorrhage in radiation sickness is thrombocytopenia, followed by microvascular and coagulation disorders.

      (1) Supplementing platelets and promoting platelet production: Transfusion of fresh platelets to patients with severe bleeding is currently the most effective anti-hemorrhage measure. Etamsylate has the effect of promoting platelet production and can also be used in the treatment of radiation sickness.
      (2) Improving vascular function: Drugs that improve and strengthen capillary function can be started during the pseudo-recovery period, such as carbazochrome (adrenochrome monosemicarbazone), 5-hydroxytryptamine, Vit.C, P, etc.
      (3) Correcting coagulation disorders: 6-aminocaproic acid (EACA), Vit.K3, etc. can be used.

   5. Blood transfusion and blood formed elements
      are important measures in the treatment of grade III or higher radiation sickness.
      (1) Blood transfusion: It can replenish blood cells, nutrients, and immune factors, stimulate and protect hematopoietic function; timing for hemostasis and anti-infection blood transfusion: (1) White blood cells below 1×10⁹/L, or granulocytes below 0.5×10⁹/L, or platelets below (30–50)×10⁹/L; (2) Hemoglobin below 80g/L; (3) Severe bleeding or critically ill, debilitated patients. Each transfusion is 200–300ml, administered 1–2 times per week.
      (2) White blood cell transfusion: After transfusion, the patient's white blood cell count may temporarily rise, peaking 4–6 hours post-transfusion and then gradually declining. Therefore, white blood cell transfusion does not increase peripheral white blood cell counts but can enhance the body's resistance, delaying and mitigating infections.
      (3) Platelet transfusion: The timing for transfusion is: (1) White blood cells below 1×10⁹/L or platelets below 20×10⁹/L; (2) Skin or mucous membrane bleeding; (3) Microscopic hematuria or retinal hemorrhage. A single platelet transfusion contains 10^11–10^12 platelets, and in cases of severe thrombocytopenia, daily transfusions may be required. Fresh platelets are generally more effective. Cryopreserved allogeneic platelets can also be used. According to the Chernobyl accident treatment experience, platelet counts in grade II and grade III radiation patients dropped to 20×10⁹/L approximately 14–18 days post-irradiation. Such patients required about 5–6 platelet suspension transfusions during the thrombocytopenic phase, each containing 3×10^11 platelets in 300ml of plasma.
      For both blood transfusion and blood formed elements, attention must be paid to the infusion rate to avoid exacerbating pulmonary edema and cerebral edema. To ensure transfusion efficacy, it is best to select HLA-matched or partially matched donors to reduce immune reactions. Before transfusion, blood or formed element suspensions should be irradiated with 15–25Gy γ-rays to remove immunologically active cells and minimize post-transfusion reactions.
   6. Hematopoietic stem cell transplantation
      There are three sources of cells for hematopoietic stem cell transplantation: bone marrow, fetal liver, and peripheral blood.
      (1) Bone marrow transplantation (BMT): Bone marrow contains abundant hematopoietic stem cells and is easy to collect, making it a commonly used method for hematopoietic stem cell transplantation. Bone marrow transplantation can be either autologous or allogeneic. Autologous bone marrow transplantation is easier to engraft and does not cause immunological reactions. Currently, allogeneic bone marrow transplantation is more widely used.
      (1) Indications: Patients exposed to lower doses of radiation who retain the ability to reconstitute hematopoiesis do not require transplantation. Patients exposed to more than 7Gy may consider bone marrow transplantation (experience from the Chernobyl accident suggests considering bone marrow transplantation only for exposures above 9Gy).
      (2) Donor selection: The best choice is an identical twin, as this type of transplantation involves no immunological differences between donor and recipient, being a syngeneic transplant similar to autologous bone marrow transplantation. However, such donors are rare. Generally, HLA (human leukocyte antigen)-matched or partially matched donors are selected. These donors are primarily sought among siblings, with a 25% probability of HLA matching according to genetic laws. This type of transplantation also yields good results, though some immunological reactions may still occur.
      (3) Timing of transplantation: Since the infused hematopoietic stem cells take 10–15 days to proliferate and produce blood cells, transplantation should be performed as early as possible. It is generally recommended to transplant within 1–5 days after irradiation, with a maximum delay of no more than 10 days.
      (4) Number of cells to infuse: The recommended dose is (2–5)×10^8/kg, with a total cell count of no less than 1.5×10⁹ cells.
      (5) Collection and infusion route: To ensure the quality of the infused bone marrow, multiple small-volume aspirations should be performed to avoid excessive contamination with peripheral blood. The bone marrow should be infused immediately after collection, with the infusion route being intravenous.
      (6) Prevention and treatment of complications: Immunosuppressants can be used before transplantation to clear the bone marrow cavity and reduce graft rejection. After engraftment, a common complication is graft-versus-host disease (GVHD). During the convalescence stage of bone marrow transplantation, interstitial pneumonia may also occur.
      GVHD occurs when the immunocompetent cells in the graft proliferate to a certain extent and attack the host's target tissues, resulting in a systemic disease in the recipient. Its incidence can be as high as 70–80%, with a mortality rate of 20–30%. GVHD can be acute or chronic. Cases occurring within 60 days after transplantation are acute (aGVHD), while those occurring several months later are chronic (cGVHD).
      GVHD primarily injures the skin, liver, and small intestine. Clinical manifestations mainly include skin papules, erythema, desquamation, abdominal pain, diarrhea, elevated serum bilirubin and aspartate aminotransferase, and in severe cases, intestinal obstruction. Chronic GVHD is also commonly associated with elevated alkaline phosphatase levels.

      Currently, the prevention and treatment measures for GVHD mainly include the following aspects.
      a. Selecting suitable donors; b. Inactivating or removing T lymphocytes from the graft before infusion. Common methods include agglutination and removal of T lymphocytes using sheep red blood cells or soybean lectin, and the application of monoclonal antibodies against lymphocytes and complement to inactivate T lymphocytes in donor bone marrow; c. Using immunosuppressants. Such as methotrexate (MTX), cyclosporin A (cyclosporin A, CsA), etc. They can also be used in combination, such as MTX and CsA, or CsA and adrenal corticosteroids; d. Using adrenal corticosteroids to control symptoms and improve the body's condition; e. In recent years, there have been reports that the use of lymphocyte chalone in animal experiments can alleviate GVHD in animals.

      (2) Fetal liver transplantation (FLT): The fetal liver at 4 to 5 months of gestation contains abundant hematopoietic stem cells, which can also serve as a source for hematopoietic stem cell transplantation. With fetal liver transplantation, the likelihood of hematopoietic stem cell engraftment is very low. Even if engraftment occurs, it can only form a temporary chimera, providing hematopoietic function for a period of time, helping patients through severe hematopoietic dysfunction, before being gradually rejected. However, experimental studies have shown that fetal liver preparations can stimulate hematopoiesis and nonspecific immune function. Additionally, since fetal liver contains fewer lymphocytes, the incidence of GVHD is lower than with bone marrow transplantation, making it suitable for grade III and even grade II radiation patients.

      (3) Peripheral blood hematopoietic stem cell transplantation: There are also a small number of hematopoietic stem cells in peripheral blood, accounting for about 1% of the total hematopoietic stem cells in the body. The morphology of hematopoietic stem cells cannot yet be identified, as they are mixed among mononuclear cells. Typically, donors are first injected with "mobilizing agents," such as dexamethasone, to increase the content of hematopoietic stem cells in peripheral blood. Then, a blood cell separator is used for continuous flow filtration to collect mononuclear cells for transplantation. However, peripheral blood contains more lymphocytes, and the immune response after transplantation may be more severe.

   7. Application of hematopoietic factors
      Currently, research on cytokines is becoming increasingly in-depth, and many recombinant cytokines have been developed. In usual radiation accidents, relevant hematopoietic factors have been applied to the treatment of radiation sickness.
2. Treatment of intestinal radiation sickness
   Patients with intestinal radiation sickness often die within 1 to 2 weeks from dehydration, acidosis, sepsis, toxic shock, etc. Therefore, the first step should be to adopt comprehensive symptomatic treatment for intestinal injury, along with early seasonal epidemic bone marrow transplantation. After surviving the intestinal death phase, the focus shifts to treating hematopoietic dysfunction.
3. Treatment of cerebral radiation sickness
   Patients with cerebral radiation sickness often die within 1 to 2 days. The key points of emergency treatment are sedation, antispasmodics, anti-shock, and comprehensive symptomatic treatment. When spasms occur, they can be controlled with phenobarbital, chlorpromazine, etc. For vomiting and diarrhea, antiemetics and antidiarrheals should be administered. For shock, fluid replacement, plasma transfusion, and the use of vasopressors such as norepinephrine, metaraminol, and mephentermine are recommended.