Blood loss due to bleeding is a reversible process as long as the amount of blood loss is compensated by physiological mechanism and/or fluid therapy. However, the amount and rate of bleeding far greater than compensatory mechanisms leads to a vicious cycle which worsens bleeding and impairs major organ dysfunctions (Fig. 1).
Annual survey of the critical incidents related to anaesthesia by the Japanese Society of Anaesthesiologists (JSA) repeatedly demonstrated that massive bleeding is a major cause of intraoperative cardiac arrest [1,2]. The JSA studies demonstrated that critical bleeding in the perioperative period was the leading cause of intraoperative cardiac arrest and perioperative death in the first week postoperatively (Table 1) [3,4]. About a half of them were related to haemorrhagic shock due to trauma, rupture of the large blood vessels, and so on. The rest were related to intraoperative bleeding due to surgical manipulation. Although the possibility of massive and rapid bleeding was anticipated and some preventive and treatment measures were to be taken to deal with such critical bleeding, prognosis was still grave.
Table 1. Incidence of intraoperative cardiac arrest and postoperative mortality in 7 days
Number of patients
Mortality after 7 days (%)
Preoperative haemorrhagic shock
Serious complications other than cardiac arrest
Intraoperative critical bleeding
Serious complications other than cardiac arrest
The Subcommittee on Surveillance of Anaesthesia-Related Critical Incidents of the JSA analysed the data. Contributing factors include far greater rate and amount of bleeding than anticipated (Fig. 2), delay in decision to start blood transfusion and to order additional blood products, hesitation to use ABO-compatible blood including group O Blood without cross-matching, delayed transportation of the blood products from the blood banks, and lack of man power. In patients with critical bleeding, blood loss was >12 l/60 kg(body weight) in 35·2% of the patients, and the maximal estimated bleeding rate was >240 ml/60 kg(body weight)/min in 44·9% of the patients. Despite critical bleeding and shortage of blood products due to delayed transportation of the blood products, cross-matching test was waived in 13·4% of the patients, and ABO-compatible blood products including group O blood was used only in 1·3% of the patients. It suggests that using uncross-matched blood might be a major concern in the physicians in Japan even in the life-threatening situation.
Although the national guidelines for blood transfusion made by the Japanese Ministry of Health, Labour and Welfare exist, the issues on critical bleeding were not fully discussed and clear guidelines were not described. Massive bleeding is commonly defined as the loss of one blood volume with in 24-h period. There are many cases where the concept of massive bleeding may not lead to appropriate blood transfusion in a timely fashion. The concept of critical bleeding is arbitrarily defined; the physicians who take care of the briskly bleeding patients feel that bleeding is very likely to result in life-threatening situation in a short period of time, i.e. within a few minutes to a few hours. Immediate and appropriate therapy to stabilize the patient and to avoid secondary damages is required. Therefore, the JSA and the Japan Society of Transfusion Medicine and Cell Therapy decided to make guidelines for treatment of critical bleeding.
Outlines of the guidelines for treatment of critical bleeding
The JSA established “Guidelines for Actions Against Intraoperative Critical Hemorrhage” (Guidelines) in collaboration with the Japanese Society of Blood transfusion and Cell Therapy in 2007. Fundamental concept is life-saving measure is much important than theoretical complications in the life-threatening critical bleeding.
There are a few basic strategies as follows:
1Physicians and nurses, medical engineers in the operating room and emergency room, staff in the blood transfusion department, and staff in the blood bank work as a team. Intense communication between them is mandatory.
2The commander is in charge of the important decisions related to blood transfusion strategies.
3Surgeons concentrate on haemostasis rather than on proceeding the planned procedure. Damage control surgery should be considered.
4Anaesthesiologists insert a few large bore intravenous lines, draws blood for blood cell counts and coagulation studies, and order blood products according to the amount and speed of haemorrhage, vital signs, laboratory data, and the prospect of haemostasis.
5ABO-compatible blood products should be used without hesitation.
6Euvolemic status should be maintained to keep adequate perfusion pressures of major organs and to maintain their functions.
7Hypothermia should be best avoided to worsen bleeding tendencies.
8The institutional structure of blood transfusion system and transport time from the blood bank should be understood by the staff concerning blood transfusion.
9The institutional guidelines for critical and massive bleeding should be established according to the Guideline.
10Simulation training involving all departments related to blood transfusion should be performed.
Commander and the team
When critical bleeding occurs, one single physician should become the commander who will direct the overall therapy including blood transfusion. The commander declares a state of emergency. Most often, the anaesthesiologist will become the commander in the operating room (OR) because the anaesthesiologist knows the general condition of the patient and is aware of the situation around the OR including storage of blood products in the institution, and transport of blood products from the blood bank. After the life-threatening condition was evaded, the commander declares the end of emergency.
The personnel in the OR, the emergency room (ER), laboratories, department of blood transfusion, and Red Cross blood center work together as a team in the face of critical bleeding (Fig. 3). Close communication amongst all departments is essential. Anaesthesiologists would start new large-bore intravenous lines (16 or 14 gauge cannulae) for fluid resuscitation and blood transfusion, and take blood samples for blood gases, complete blood cell count, coagulation studies, and cross-matching. Arterial and central venous lines may be inserted. The commander would order blood products according to the general condition of the patients, laboratory data, and availability of blood products. Surgeons would concentrate on haemostasis rather than on completing the planned procedure. Damage control surgery should be considered. Medical engineers would prepare for intraoperative autologous blood transfusion and rapid infusion pumps. Nurses would measure the amount of blood loss, and keep contact with the blood bank and check blood product bags.
Postoperative management in the intensive care unit is probably required. Postoperative mechanical ventilation may be required.
Red blood cell transfusion
Cross-matched red cell concentrates (RCC) is used in the routine cases. However, in the critical bleeding, there would not be enough time to prepare cross-matched RCC. Life-saving is far important than to avoid remote risk of delayed haemolysis and other minor reactions. It is important to consider the risks and benefits of specific blood products in terms of availability and timing.
If type and screening is performed preoperatively, the RCC would be available within 5 to 15 min after blood typing or computer cross-matching. The ABO type-specific RCC can be used. If the ABO type-specific RCC is not available in a short period of time, ABO-compatible RCC including group O RCC should be used.
Distribution of ABO and Rh types varies from country to country. In Japan, the distribution of blood types is different from European countries. The blood types of Japanese roughly consist of group A 40%, group O 30%, group B 20%, and group AB 10%. The ratio of Rh-D (+) is over 99% in Japan. The population of people with group AB, Rh-D (−) is <1/2000 population.
Even the existence of antibody to red blood cells is known, the risk of haemolysis needs to be assessed against the risk of withholding blood transfusion until compatible RCC can be provided. The Guidelines recommend that uncross-matched blood should be used when time does not allow for waiting the cross-matched RCC even in patients with red cell antibody. There is a risk of delayed haemolysis. Overall risk of delayed haemolysis is up to 1%. The patient with antibody to red cell who received uncross-matched blood products should be observed closely for a few weeks to find signs of haemolysis promptly. Delayed haemolysis occurring after a few days to a few weeks can be managed without difficulty.
Irradiation is indicated to the RCC and platelets to prevent transfusion related graft-versus-host disease (GVHD). The Guidelines indicated that irradiation may be omitted to save time. However, some people are concerned about transfusion of not-irradiated blood products. Further studies are required to solve this problem.
Autologous blood transfusion
Use of intraoperative autologous blood transfusion is encouraged when the contraindications for this method do not exist. The help of medical engineers may be required. This technique may be quite useful in patients with ruptured major blood vessels.
Use of preoperative autologous blood donation is limited. Effectiveness of preoperative autologous blood donation has been controversial. Preoperative autologous blood donation is encouraged in patients with rare blood type undergoing major surgery with the possibility of large blood loss. Our studies suggested that in obstetric patients with placenta previa and other factors leading large blood loss may be benefited from the preoperative autologous blood donation. The median amount of preoperative autologous blood donation was 800 ml.
Fresh frozen plasma
The major recommended indication of fresh frozen plasma (FFP) is to supplement multiple coagulation factors for bleeding tendency due to deficiencies in coagulation factors. Trigger points are prothrombin time (PT) activity equal or <30% or PT-INR equal or <2·0, activated partial prothrombin time (aPTT) greater than two times the upper limit of the institutional standard level or activity equal or <25%, or fibrinogen level less than 100 mg/dl in Japan.
The indications for FFP are similar in other countries. The practice guidelines for perioperative blood transfusion by the American Society of Anaesthesiologists state that FFP transfusion is indicated for (1) correction of excessive microvascular bleeding (coagulopathy) in the presence of PT >1·5 times normal or INR > 2·0, or an aPTT > 2 times normal; (2) correction of excessive microvascular bleeding secondary to coagulation factor deficiency in patients transfused with more than one blood volume and when PT and aPTT cannot be obtained in a timely fashion .
In bleeding patients, these criteria may be fulfilled when the blood loss is greater than one blood volume. Fibrinogen may become <100 mg/dl before other coagulation factors fall below the minimum haemostatic levels by bleeding [6,7]. PT may not reflect decreased level of fibrinogen.
The fibrinogen concentration which causes microvascular bleeding is considered 50–80 mg/dl. It should be avoided to let fibrinogen concentration fall below this level in actively bleeding patients.
However, performing these coagulation studies may not be practical in actively bleeding patients with unstable haemodynamics. It also delays administration of FFP because of preparation time. Therefore, it is recommended to draw blood samples for later analysis and to give FFP without waiting the final results.
Cryoprecipitates are useful to increase fibrinogen level efficiently with small amount of volume. Each unit of cryoprecipitate contains 150 mg of fibrinogen in about 15 ml of plasma. Unfortunately, cryoprecipitates are not commercially available in Japan. The only current indication for fibrinogen concentrates is congenital fibrinogen deficiencies with bleeding tendency. Fibrinogen products were approved for treatment of acquired low fibrinogenemia in the past. An estimated 10 000 cases of hepatitis C infection have been attributable to use of inappropriately heated fibrinogen in Japan. It became a social issue and citizens may hesitate to receive fibrinogen products even though the currently available products are properly produced and safe.
Recombinant activated factor VII concentrates is indicated with the specific factor deficiency with antibodies and is very expensive. Some anecdotal cases indicated the usefulness of factor VII products in patients with massive bleeding. Although some people recommend to use recombinant activated factor VII when other ordinary haemostatic measures have failed, one retrospective study suggested last-ditch recombinant activated factor VII therapy was ineffective to rescue the patients who were resistant to conventional treatment . Recent review by Johannsson did not support routine use of recombinant activated factor VII concentrates for patients with massive bleeding . It may increase risk of thromboembolic events. Therefore, use of recombinant activated factor VII was not mentioned in the Guideline.
ABO-compatible FFP can be used when type-specific FFP is not available.
Platelet concentrates are indicated when platelet count is <50 000 associated with bleeding tendency in usual surgical patients. The minimum level of 100 000/mm3 is recommended for ophthalmologic and intracranial surgery. In the critical bleeding, platelet concentrates should be administered to maintain platelet count >50 000/mm3. The trigger of platelet transfusion may be higher than usual (e.g. 75 000/mm3) in patients with critical bleeding. ABO-compatible platelet concentrates can be used when type-specific platelet concentrates are not available.
Serial and frequent measurements of blood cell count are necessary because platelet count changes rapidly in the setting of critical bleeding.
Crystalloids and colloids
It is important to maintain tissue perfusion by appropriate volume status and vasoactive agents if necessary. Restoration of circulating volume is initially achieved by rapid infusion of crystalloid such as lactated, acetated or bicarbonate Ringer’s solution, and normal saline. Artificial colloids such as hydroxyethyl starch (HES) is usually indicated when blood loss is greater than 20% of one blood volume. HES is indicated in critically bleeding patients. The amount of HES is commonly limited to 1000 ml or 20 ml/kg of body weight because HES is potentially induces platelet inhibition and renal dysfunction. HES are known to interfere with coagulation according to molecular weight. Because the currently available HES in Japan contain relatively low molecular weight, interference with coagulation may not be significant. Duration of plasma volume expansion may be short-lived. The upper limit of HES is not described in the Guideline.
The use of albumin solution has been controversial [10,11]. Currently 5%, 20%, and 25% albumin solutions are available in Japan. Plasma protein fraction is also available. The Guideline did not prohibit the use of albumin solutions in the setting of critical bleeding.
Avoidance of adverse effects and complications of rapid blood transfusion
Although blood transfusion may save lives in patients with critical bleeding, it presents risks to the patients. The potential risks include accidental transfusion of the incompatible unit of blood, transmission of viral, bacterial, and other microbial infections, GVHD, transfusion-related acute lung injury (TRALI), and so on. These complications can be fatal either in a short-term or in a long-term. Correct identification of the recipient blood group and use of compatible blood products are of paramount importance. It is strongly recommended to check the recipient blood group twice before blood transfusion. In an emergency situation, some physicians often check blood type only once. To avoid blood-transfusion-related GVHD, irradiation to the blood products is highly recommended. Some institutions receive only irradiated blood products, and some receive nonirradiated blood products and irradiate blood products immediately before blood transfusion to avoid the risk of hyperkalemia . Sometimes there is no time to irradiate blood products in life-threatening situation. It is helpful to store irradiated blood products and to order irradiated blood products from the blood bank for emergency.
Acute complications related to rapid blood transfusion including hypothermia, acid base abnormalities, electrolyte imbalance should be considered and appropriately treated.
It is important to avoid hypothermia. Hypothermia reduced platelet aggregation and vascular reactivity, leading to increased blood loss. Efficient blood warmer should be used. Warm forced-air system and other devices should be used to keep normothermia.
Hyperkalemia due to the old RCC and irradiated blood can be fatal in massive blood transfusion . Although it is rare to see life-threatening hyperkalemia due to blood transfusion, it may occur in the presence of impaired renal function, severe acidosis. It may also occur in infants and small children. Serial measurements of blood samples are necessary. Changes in electrocardiogram changes including tall T-wave may not be sensitive and often overlooked. Hyperkalemia should be treated by alkalization of the blood by hyperventilation and administration of sodium bicarbonate, furosemide, and calcium chloride (or calcium gluconate). After massive blood transfusion, hypokalemia may occur.
Hypocalcemia may occur with rapid transfusion of the RCC and FFP. In the usual setting, hypocalcemia can resolve spontaneously in 10 min. However, in massive and rapid blood transfusion, severe hypocalcaemia resulting in cardiac depression and circulatory collapse is a real possibility. Hypocalcemia should be treated by calcium products.
Use of rapid transfusion device is optional. Although these devices are capable of transfusing blood rapidly in the critically bleeding patients, these are not designed for this purpose. Some fatal accidents have occurred because of lack of experience and neglect of the proper use. These rapid transfusion devices should be used by the experienced medical engineers or physicians.
Institutional guidelines and simulation
The guidelines set by the JSA and the Japan Society of Transfusion Medicine and Cell Therapy can be modified according to the situation of each institution. Our studies demonstrated that more than 80% of the major institutions had their own blood transfusion guidelines. However, only one-third of the institutions performed simulations. Although these guidelines are well-known and understood by the staff in the blood bank, these are not well understood by surgeons and obstetricians particularly working for the small institutions.
It is not clear how much blood products should be stored in each institution. The more the storage, the higher the amount of the wasted blood products. It is also important to know the transfer time from the Red Cross Blood Center. It takes more than 60 min to receive the blood products from the Red Cross Blood Center. in the emergent situation in some institutions. It is also important to know how long it takes to determine blood types and to cross-matching. These factors should be taken into consideration when to order blood products.
We have been following the situation of critical bleeding and blood transfusion in different departments including anaesthesia, paediatric anaesthesia, emergency medicine, obstetrics, and blood transfusion in Japan . The study was supported by the Grant of the Ministry of Health, Labour and Welfare (H.19-MP-General-031) since 2007.
We performed a questionnaire survey regarding the present status of critical bleeding (35 000 ml) occurring in major hospitals in Japan in 2006 . A total of 692 241 cases managed by anaesthesiologists in 247 institutions were registered. There were 2657 cases of massive haemorrhage over the circulating blood volume in the operating room, and 404 of them were considered critical. Thus, the number of patients with massive bleeding was 6·6 times that of patients with critical bleeding. In 1257 patients with massive blood loss (35 000 ml), 196 patients (15·6%) died within 30 postoperative days and 160 patients (12·7%) had major sequelae including permanent brain damage. While the amount of transfused RCC was 25·2 ± 24·2 units (one unit means RCC from 200 m of donated blood), the amount of RCC stocked for emergency in the hospital was 12·7 ± 10·1 units for group A, 9·7 ± 7·3 units for group B, 11·9 ± 9·6 group AB, and 11·3 ± 11·0 for group O. Some institutions had much less RCC storage. The uncross-matched, same blood type transfusion and compatible, different blood type transfusion were performed in 8·2% and 4·3%, respectively. The lowest haemoglobin concentration was below 5 g/dl in 16·7% of the patients, but uncross-matched, same blood type transfusion was performed only in 19·0% and compatible, different blood type RCC transfusion in 5·2%. Even in patients who required cardiac massage, uncross-matched, same blood type transfusion was performed only in 17·1% and compatible, different blood type RCC transfusion in 8·5%. Intraoperative blood salvage was performed in 5·7% in patients undergoing non-cardiac surgery. The “Guidelines for the Management of Critical Hemorrhage” proposed in 2007 or the manuals for in-hospital emergency blood transfusion were not widely recognized in surgical staff. The institutional blood transfusion manual did not contain the part regarding to critical bleeding in about 60% of the surveyed institutions. Insufficient blood transfusion might have occurred in 16·7–28·3% of patients with massive bleeding.
Our study in 2007 demonstrated that the amount of blood loss greater than one blood volume occurred in 6·6 patients/1000 surgical procedures . Mortality rate of the patients with blood loss >5000 mL was 2·8/10 000. Uncross-matched blood was used in 102 patients (8·2%) in the patients with blood loss >5000 mL. ABO-compatible blood was used in 1·5% of the patients. These rates seemed to be too low.
These studies suggest the necessity of further promotion of the Guidelines, institutional simulation according to the institutional blood transfusion guidelines, and appropriate practice in patients with critical bleeding.
This article is supported by the Grant of the Ministry of Health, Labour and Welfare (H.19-MP-General-031).