Stress ulcer prophylaxis in the ICU patients

INTRODUCTION —

• Stress ulcerations are mucosal erosions that generally occur in the fundus and body of the stomach, but sometimes develop in the antrum, duodenum, or distal esophagus.
• They tend to be shallow and cause oozing of blood from superficial capillary beds, but deeper lesions can erode into the submucosa, causing massive hemorrhage and/or perforation.

The risk of stress ulceration depends upon the severity and type of a patient's underlying illness.

• Studies of various intensive care unit populations have estimated the risk of stress ulceration complicated by clinically significant bleeding at 1.5 to 15 percent.
• Stress ulcerations are the most common cause of gastrointestinal (GI) bleeding in intensive care unit (ICU) patients, and the presence of GI bleeding due to these lesions is associated with a five-fold increase in mortality compared to ICU patients without bleeding.

Considerable effort and expense are devoted to the prevention of stress ulcerations in pati
ents in the ICU because the consequences of GI bleeding can be severe.

• However, continued use of stress ulcer prophylaxis in hospitalized patients who have been discharged from the ICU is generally unwarranted and alarmingly common.

PATHOPHYSIOLOGY —

• Erosions begin to develop in the proximal regions of the stomach within hours of major trauma or serious illness.
• In one study, endoscopy performed within 72 hours of a major burn or cranial trauma revealed evidence of acute mucosal disease in 75 to 100 percent of patients.
• Up to 50 percent of these early mucosal lesions have endoscopic evidence of recent or ongoing bleeding,
• but only a small percentage of these patients experience hemodynamic compromise due to acute blood loss.

Stress ulcerations that evolve after the first several days of hospitalization tend to be deeper and occur more distally within the GI tract.

• As an example, one study of 67 patients with GI bleeding which occurred a mean of 14 days after admission found that duodenal ulceration was the most common source of bleeding.
• It is uncertain if early and late ulcerations have the same pathophysiology, but both types are thought to result from derangements in the balance between gastric acid production and mucosal protective mechanisms.

One or more of the following processes may be involved:

Hypersecretion of acid —

• Hypersecretion of acid due to excessive gastrin stimulation of parietal cells is seen primarily in patients with head trauma.
• Acid secretion tends to be normal or subnormal in most other patients, in whom stress ulceration results from a breakdown of mechanisms normally protecting the gastric mucosa from the effects of acid.

Defects in gastric glycoprotein mucus —

• The stomach normally is protected by a glycoprotein mucous layer, which both forms a physical barrier to hydrogen ion diffusion and traps bicarbonate, allowing neutralization of gastric acid in the area adjacent to the stomach wall.
• In critically ill patients, increased concentrations of refluxed bile salts or the presence of uremic toxins can denude the glycoprotein mucous barrier and permit gastric injury.

Ischemia —

• Shock, sepsis, and trauma can lead to impaired perfusion of the gut.
• Experimental models of shock suggest a relationship between gastric mucosal ischemia and diminished secretion of protective mucus and bicarbonate.

H pylori —

• The influence of infection with H. pylori on the development of stress ulcers in the intensive care unit has not been well studied.
• One multicenter case-control study identified 29 patients with acute upper GI bleeding following admission to an intensive care unit, and found that these patients were more likely than nonbleeding ICU patients to have evidence of H. pylori infection (36 versus 16 percent).
• In a separate report, a statistically nonsignificant trend toward an increased risk of macroscopic gastrointestinal bleeding was observed among 67 H. pylori positive patients compared to 33 H. pylori negative controls.
• Furthermore, nurses in the intensive care unit were more likely to be infected with H. pylori than age-matched controls (40 versus 19 percent), suggesting the possibility of nosocomial transmission.

RISK FACTORS —

A prospective multicenter cohort study of 2252 ICU patients identified two major risk factors for clinically significant bleeding due to stress ulcers:

1. mechanical ventilation for more than 48 hours (odds ratio 15.6); and
2. coagulopathy (odds ratio 4.3).

• The risk of clinically important bleeding in patients without either of these risk factors was only 0.1 percent.

A number of smaller studies have reported additional risk factors for stress ulcerations, including :

• Shock
• Sepsis
• Hepatic failure
• Renal failure
• Multiple trauma
• Burns over 35 percent of total body surface area
• Organ transplant recipients
• Head or spinal trauma
• Prior history of peptic ulcer disease or upper GI bleeding

PROPHYLACTIC AGENTS — A variety of medications may be used to reduce the incidence of stress ulceration, including antacids, H2 blockers, sucralfate, proton pump inhibitors, and prostaglandin analogs.

Antacids —

• The action of antacids are to decrease gastric acidity by direct neutralization of stomach acid.
• Antacids are generally considered effective in the prevention of stress ulceration because numerous studies have shown roughly equivalent outcomes with these agents and H2 blockers.
• However, one meta-analysis found only a nonsignificant trend toward efficacy with antacids compared to placebo.

Drug costs are low, but these agents require administration of 30 to 60 mL orally or via nasogastric tube every one to two hours.

• The increase in nursing costs necessary for such administration negates some of the potential cost savings.
• Side effects of antacids can include hypermagnesemia, hypophosphatemia, constipation, diarrhea, nasogastric tube obstruction, and an increased risk of nosocomial pneumonia.

H2 blockers —

• H2 blockers raise gastric pH by decreasing the stimulatory effects of histamine on parietal cell acid secretion.
• Their effectiveness in preventing stress ulceration has been documented in most (but not all) trials.
• One meta-analysis, for example, reported a significantly lower risk of clinically significant GI hemorrhage with cimetidine versus placebo (3 versus 15 percent).

Administration of H2 blockers by continuous infusion provides better control of gastric pH than bolus infusion, but is not more effective in preventing clinically significant bleeding.

• H2 blockers are also effective if given orally or via nasogastric tube.

• H2 blockers are generally well tolerated, but occasionally the drugs may produce interstitial nephritis, confusion, or thrombocytopenia.
• Furthermore, the pharmacokinetics of drugs such as theophyline and warfarin may be significantly affected by cimetidine but not other H2 blockers.
• The costs of H2 blockers can be substantial, and dosing via continuous infusion may increase the number of intravenous catheters required by the patient.

Sucralfate —

• Sucralfate is a complex polyaluminum hydroxide salt of sucrose sulfate which exerts its effects via coating and protection of the gastric mucosa rather than through neutralization or inhibition of gastric acid.
• Sucralfate becomes highly polar at acid pH and binds preferentially to the granulation tissue of exposed ulcer beds, protecting them from further damage from acid, bile salts, or pepsin.

• The most rigorous randomized trial to date studied 1200 mechanically ventilated patients and found a significantly higher risk of clinically important GI bleeding with sucralfate versus H2 blocker (ranitidine) (3.8 versus 1.7 percent).
• This trial was important because of its large sample size, the fact that care givers, research personnel, and analysts were blinded to treatment assignments, its high rates of compliance, and the fact that clinical bleeding and pneumonia were strictly defined.
• One meta-analysis described similar findings, but reported a reduced mortality rate with sucralfate versus antacids and H2 blockers, possibly due to the less frequent development of nosocomial pneumonia (see below).
• Other, less rigorous trials have been done and in general reported that sucralfate and H2 blockers have similar efficacy.

Sucralpate is generally well tolerated.

• Elevations of plasma aluminum concentration have not been observed in intubated patients receiving 6 grams/day of sucralfate for 14 days, even in the presence of renal impairment.
• Costs may differ substantially between institutions, but the use of sucralfate generally is less expensive than the use of parenteral H2 blockers.

Proton pump inhibitors —

• Proton pump inhibitors, such as, omeprazole and others, contain a reactive sulfhydryl group that forms a disulfide bond with a cysteine residue on the H-K-ATPase pump, thereby inactivating the enzyme.
• Data regarding the efficacy and potential adverse effects of these drugs in the prevention of stress ulceration are less extensive than the sucrafate, H2 blockers, and antacids.
• Short-term use of proton pump inhibitors is rarely associated with significant side effects.
• Hypotheses regarding an increased incidence of nosocomial pneumonia due to elevations in gastric pH have not been adequately tested.

The ability of omeprazole oral suspension to decrease stress-induced GI bleeding was assessed in two prospective, open-label trials of mechanically ventilated with at least one additional risk factor for stress-related mucosal damage.

• In the first study, 75 patients received two doses of omeprazole oral suspension 40 mg six to eight hours apart, followed by 20 mg/day delivered via nasogastric tube.
• There were no episodes of bleeding and no evidence of toxicity.
• Similar results were noted in a subsequent study of 60 patients treated with omeprazole administered using the dosing regimen described above.

The relative efficacy of intravenous omeprazole, intravenous H2 blocker, and sucralfate in preventing bleeding associated with stress ulcers was evaluated in a prospective, randomized, three-arm trial published in abstract form.

• Omeprazole (40 mg every 12 hours) and ranitidine (150 mg/day) were administered intravenously; sucralfate 1 g every six hours was administered by nasogastric tube.
• The frequency of upper gastrointestinal bleeding was similar in patients treated with ranitidine and sucralfate (10.5 percent and 9.3 percent, respectively).

One study randomized 67 high-risk patients to prophylaxis with either intravenous H2 blocker or oral omeprazole.

• A significantly larger proportion of patients in the ranitidine group developed clinically important bleeding (31 versus 6 percent); however the ranitidine group had more risk factors for GI bleeding despite randomization, potentially confounding the results of the study.
• A subsequent larger trial compared oral omeprazole and intravenous the cimetidine in 359 ICU patients, and noted similar rates of GI bleeding in both groups (4.5 versus 6.8 percent, respectively;) .
• It has been suggested that oral PPI therapy may be more cost-effective than intravenous cimetidine for the prevention of stress ulcer-related gastrointestinal bleeding.

Prostaglandin analogs —

• Prostaglandin analogs such as the mesoprostol have both antisecretory and cytoprotective effects.
• The latter may result from capillary bed vasodilation, which protects against local ischemia.
• Several small trials and animal experiments suggest that misoprostol may be as effective as H2 blockers or antacids, in preventing stress ulceration, but the paucity of data and the propensity to cause diarrhea limit its clinical use in this setting.

Nutrition —

• Several studies have reported that enteral nutrition may reduce the risk of bleeding due to stress ulcerations.
• As an example, one study of 526 seriously burned patients compared treatment with antacids and cimetidine, versus enteral nutrition in the absence of prophylactic medications.
• The rate of overt GI hemorrhage was significantly lower in the group that received enteral nutrition as the sole form of GI prophylaxis (3.3 versus 8.3 percent).

A separate study analyzed data from 1077 critically ill Canadian patients who required mechanical ventilation for more than 48 hours.

• Patients who received enteral nutrition were significantly less likely to develop an upper gastrointestinal hemorrhage (risk ratio 0.30; 95% CI 0.13-0.67).
• However, treatment was not randomized, so it is possible that patients with a lower intrinsic risk of bleeding were better able to tolerate enteral feeding.

The effect of enteral nutrition is not mediated by an increase in gastric pH.

• Nutrition may prevent exhaustion of gastric epithelial energy stores and thereby prevent necrosis and ulcer formation; this mechanism may explain the protective effect against stress ulceration that has been reported with total parenteral nutrition (TPN).

NOSOCOMIAL PNEUMONIA —

• The major concern about prophylactic therapy for stress ulceration has been the potential increased risk of nosocomial pneumonia.
• Agents that raise gastric pH may promote the growth of bacteria in the stomach, particularly gram-negative bacilli that originate in the duodenum.
• Esophageal reflux and aspiration of gastric contents along the endotracheal tube may lead to endobronchial colonization and to pneumonia.

A number of studies have documented an increased frequency of nosocomial pneumonia in patients treated with H2 blockers or antacids as compared with the sucralfate.

• As an example, one study randomized 258 intubated patients to treatment with one of the following regimens: ranitidine at a rate of 6.25 mg/hour,; antacid 20 mL of antacid via nasogastric tube every two hours; or 1 gram of sucralfate via nasogastric tube every four hours.
• Nosocomial pneumonia occurring four or more days after intubation was significantly less frequent in patients receiving sucralfate (five versus 16 percent with antacids and 21 percent with ranitidine).
• No significant differences in macroscopic gastric bleeding were noted among the three treatment groups.

• A subsequent study of 1200 mechanically ventilated patients randomized to prophylaxis with either 1 gram every 6 hours of sucralfate or 50 mg every 8 hours of intravenous H2 blocker found only a nonsignificant trend toward a lower incidence of ventilator-associated pneumonia among sucralfate-treated patients.

SUMMARY

• Stress ulcers are mucosal erosions which primarily occur in the stomach, but can also be found in the distal esophagus or duodenum. They can develop within hours of a trauma or the onset of a critical illness. Critically ill patients who bleed from these lesions have a five-fold increase in mortality compared with patients who do not bleed.

• Stress ulcers are believed to be caused by an imbalance between gastric acid production and mucosal protection mechanisms. Mucosal ischemia may be an important cause in patients with underlying shock, sepsis, and trauma.

• Definite risk factors for the development of stress ulcers include mechanical ventilation for more than 48 hours and coagulopathy.
• In addition, possible risk factors include shock, sepsis, hepatic and renal failure, multiple trauma, burns (>35 percent total body surface area), organ transplantation, head and/or spinal trauma, and a prior history of upper GI bleeding or peptic ulcer disease.

• Pharmacologic agents available for stress ulcer prophylaxis include H2-antagonists, antacids, sucralfate, prostaglandin analogs, and proton pump inhibitors (PPIs).
• It is widely suggested that oral PPIs are for patients who are able to receive enteral medications, rather than intravenous H2 blockers, because they are superior at maintaining gastric pH >4, are not limited by tolerance, and may be more cost-effective.
• In contrast, intravenous H2 blockers in for patients who cannot receive enteral medications, rather than intravenous PPIs.
• This is based on the opinion that the far greater cost of intravenous PPIs outweighs the nominally greater efficacy that may exist.

• Stress ulcer prophylaxis should be discontinued after discharge from the ICU.

• The role of enteral nutrition in stress ulcer prophylaxis is uncertain.
• Early enteral nutrition contributes to stress ulcer prophylaxis;
• however, it alone cannot be recommended as sole stress ulcer prophylaxis in high risk patients.

• Whether acid suppression therapy confers an increased risk of nosocomial pneumonia is uncertain due to conflicting published data.

TRANSFUSION OF BLOOD AND BLOOD PRODUCTS

TRANSFUSION OF BLOOD AND BLOOD PRODUCTS
Introduction
In UK all blood and plasma products are derived from voluntary non-remunerable donors aged 18 – 65 years.
All donations are tested for known markers of disease.
Currently these are
HIV-1
HIV-2
Hepatitis B
Hepatitis C
Sterilization of other transmitting agents not detected by donor screening is not guaranteed.
Current concern-
Hepatitis G
Prion protein- responsible for new variant Creutzfeldt – Jakob disease (CJD)

Good transfusion practice
careful selection of donors
quality assurance testing of blood and blood products
blood grouping, antibody screening and crossmatching

Haemoglobin transfusion thresholds
Patients do not require a preoperative blood transfusion unless the haemoglobin is less than 8g/dl. Exceptions to this rule are patients with cardiovascular disease or expected to have covert cardiovascular disease. They require blood transfusion when their haemoglobin is less than 9g/dl.

BLOOD SPARING STRATEGIES
preoperative autologous blood donation
Benefits of autolagous is elimination of disease transmission and allergic and incompatibility reactions. The date of admission and operation should be guaranteed before this to happen. Blood should not be waste and if more blood is required than collected, in that case all benefit is lost and over that the expenditure of autologous blood is more than allogenous.
Erythopoietin
This hormone is produced and secreted by the kidneys and regulates erythropoiesis. Recombinant human erythropoietins (a & b) are widely used in the anaemia associated with renal failure and as a blood sparing strategy in patients undergoing major surgery.
It is administered subcutaneously (600 units/kg) three times weekly and on the day of surgery and is preferably accompanied by oral/intravenous iron therapy.
Risk of erythropoietin therapy is deep vein thrombosis, especially if the haemoglobin exceeds 13gm/dl. A 500ml venesection is necessary whenever erythropoietin induces the patient’s haematocrit to rise above 0.5.
Patients on erythropoietin should have their haematocrit checked weekly.

3. Acute normovolaemic haemodilution
Immediately before surgery, usually following induction, 1000 ml of blood are removed with replacement of volume by crystalloids ( with monitoring of central venous pressure). The blood is given to the patient if and when it is needed during or after surgery.

4. Antifibrinolytic drugs
These include aprotinin ( a kallikrein inhibitor) and tranexamic acid ( E-aminocaproic acid). They recommended for patients undergoing cardiac surgery that carries a high risk of transfusion.

5. Intraoperative blood salvage
· The Haemonetics cell saver system is completely automated device that aspirates, anticoagulate and filter the extravasated blood from the operative field.
· The red cells are than washed before being transfused in a packed cell volume of 0.5. This system is used extensively during liver transplantation and Jehovah’s Witnesses undergoing major surgery.
· A more simple manual system for storage and reinfusion of red cells is also in use.
· Both techniques are only applicable to the clean operative sites without bacterial, bowel or tumour cell contamination.

BLOOD AND PLASMA PRODUCTS

Stored whole blood
Whole blood is only indicated for the treatment of acute haemorrhage; hypovlaemia is accompanied by an acute reduction of red cell mass, resulting in impaired oxygen capacity at a time when tissue perfusion is compromised. Even in this situation, its use must be reserved for those patients with substantial blood loss and a haemotocrit of 0.3 or less after volume replacement with crystalloid and plasma expanders.
Stored blood has a number of unwanted features:
1. citrate anticoagulant
2. an acid pH (6.6 – 6.8);
3. high levels of K+ (from the stored red blood cells);
4. ammonia ( from erythrocyte adenosine);
5. reduced red cell 2, 3 – diphosphoglycerate (2,3 DPG which leads to impaired release of oxygen from oxyhaemoglobin).

Red cell concentrates
Packed red cells have the same oxygen carrying capacity of blood but a lower volume. They are thus ideal for the treatment of anaemic patients, who invariably have a normal blood volume and are at risk of the circulatory overload.
Even so, unless the anaemia is sever and symptomatic, transfusion is no substitute for haematinic ( promotion of blood production) therapy and is only indicated in patients who:
do not respond to haematinic treatment ( refractory anaemia);
are unable to adapt to the reduced oxygen carrying capacity of the blood and exhibit signs of incipient cardiovascular failure;
require urgent surgery.
Up to 10% of patients develop alloimmunization to leukocyte antibodies cause severe febrile reactions, which can only be prevented by the use of leukocyte-poor red cell concentrates.

Frozen red cells
The use of cryoprotective agents such as glycerol or hydroxyethyl starch allows satisfactory storage of red cells at -80 to -196 degree C (mechanical freezing or liquid nitrogen storage) for long periods ( up to 10 years). This method of storage removes leukocytes, platelets and any viral particles, thereby reducing the incidence of both transmission of viral disease and alloimmunization to leukocyte and platelet antigens. Red cells recovered from a frozen bank are of particular value to patients on renal dialysis programmes, those with refractory anaemias, and those with rare cell types and complex antibody mixtures. However frozen red cells are very expensive and impractical for most patients.

Platelet concentrates
Platelet concentrates can be obtained by centrifugation of blood from several donors or by plateletpheresis of a single donation. Because of the variable but significant contamination with red cells, platelet concentrate have to be obtained from ABO/Rh-compatible donors. Some human leukocyte antigens (HLAs) are expressed on platelets and determine platelet survival after transfusion. These HLAs lead to alloimmnization in patients requiring repeated platelet transfusions. The antibodies generated cause rapid destruction of the transfused platelets and account for the progressive inefficacy of repeated transfusions. For these patients, HLA- matched platelet concentrates are needed. In surgical practice the platelet transfusions are most commonly used to stop bleeding in thrombocytopenic patients, to cover surgery if the platelet count is below 40* 10 to the power 9 /L and in patients with platelet dysfunction.

Plasma products
These are produced from voluntary donors and are used for a variety of purposes.
As coagulation factors for specific deficiency states, either to stop spontaneous bleeding or cover an operation/intervention in a patient with such a deficiency, e.g. haemophilia A (congenital factor 8 deficiency).
to provide passive immunity to non-immunized individuals exposed to a serious infective agent (viral or bacterial), e.g. human tetanus immunoglobulin.
In the prophylaxis of haemolytic disease of the newborn due to Rhesus incompatibility and sensitization of Rh(D)-negative women.
In the management of autoimmune thrombocytopenic purpura. High dose intravenous human innunoglobulin can produce remissions of varying duration. IgG is also used to treat acute haemorrhage due to this condition when conventional therapies have failed and to cover patients with idiopathic thrombocytopenic purpura requiring surgery including elective splenectomy.
As volume replacement fluid (ALBA 4.5%) and as plasma volume expander and sort-term management in hypoproteinaemic patients (Human Albumin Solution 20%).
The most common fraction used in surgical practice is fresh frozen plasma (FFP). Each unit is obtained from a single donation and consists of 200-300 mL of plasma with 40 – 60 ml of citrate anticoagulant nutrient mixture.
FFP is in following clinical situations.
To correct isolated deficiencies of plasma, e.g. factor 2, 5, 7, 10 , 11, 12, pseudocholinesterase, antithrombim 3 and C1 esterase inhibitor.
To reverse oral anticoagulation with warfarin/coumarin compounds if prothrombin complex concentrate is not available. Normally, reversal of anticoagulant is indicated in the presence of bleeding.
To provide haemostatic support and to cover operations/interventions in patients with liver disease, major hepatic resections and severe liver injuries.
To replace the factors consumed by the pathological process in the treatment of patients with disseminated intravascular coagulation (DIC).
In patients who develop a bleeding diathesis after large-volume blood transfusion. In this situation, however, platelet transfusion is more commonly needed first.
In the treatment of thrombotic thrombocytopenic purpura, where FFP is usually combined with plasma exchange.

Adverse affects of transfusion
Blood transfusion is nowadays very safe, the overall risk of an adverse outcome being 1 in 12000. The mechanisms of transfusion reactions are varied, depending on the cause.

Table – complications of transfusion.
Acute
Non haemolytic reactions
Pyogenic (febrile ) reactions
hypersensitivity
Haemolytic reactions
Metabolic, respiratory and haemostatic complications
Circulatory overload
Septic shock (bacterially infected units)

Delayed
Delayed haemolytic
Infective
Bacterial: brucellosis, syphilis
Helminthic: filariasis
Protozoal: babesiosis, chaga’s disease, kala-azar, malaria, trypanosomiasis, toxoplamosis
Rekettsial: relapsing fever, Rocky Mountain spotted fever
Viral: B19, CMV, EBV, HIV-1, HIV-2, HTLV-1,HTLV-2,hepatitis, yellow fever
Sensitization/alloimmunization
Haemolytic disease of the newborn
Immnue suppression (increased infective risk)
Post-transfusion purpura
Platelet refratoriness
Transfusion iron overload (haemosiderosis)
Graft vs. host disease

Acute reaction

Acute non haemolytic reactions
The routine establishment of quality control in the manufacture of both intravenous fluids and disposable giving sets has virtually eliminated pyrogenic reactions. Pyrexia following blood transfusion is nowadays the result of alloimmunization to leukocyte and platelet antigens in patients requiring repeated blood transfusions. This is the commonest cause of severe febrile reactions. Although the reaction is usually self-limiting and benign, the transfusion must be stopped to exclude the possibility of a more serious haemolytic reaction.
Febrile reactions in alloimmunized patients can be prevented by using red cell concentrated, from which most of the other formed elements have been removed (leukocytes, platelets, soluble histocompatibility antigens).
Severe immediate hypersensitivity reactions and mild allergic or anaphylactoid reactions are of non well defined etiology and results in the release of vasoactive peptide and activation of complement.
Severe anaphylaxis is rare but potentially fatal reaction. Occasionally is caused by antibodies to IgA in patients who have extremely low plasma levels of this immunoglobulin. Whatevere the cause anaphylaxis results in the release of vasoactive peptides and activation of compliment, with the development of profound hypotension, laryngeal spasm and/or bronchospasm, and cutaneous flushing. Anaphylaxis is treated with –
Immediate termination of transfusion;
intravenous crystalloids;
maintenance of airway and administration of oxygen;
adrenaline (0.5 – 1.0 mg i.m.);
intravenous antihistamine and salbutamol.
The adrenaline dose is repeated if necessary every 10 min, depending on the improvement in blood pressure and pulse. Chlorpheniramine 10 to 20 mg is administered by nebulizer. Serum anaphylaxis can only be predicted in patients with low serum IgA. If possible, transfusion should be avoided in these patients.

Acute haemolytic reactions
These reactions are usually result of ABO incompatibility due to human error at the bedside or in the laboratory (faulty cross-matching). The transfused cells react with the patient’s own anti-A or anti-B antibodies or their alloantibodies to red cell antigens.
Incompatible blood transfusion is a serious complication and carries an average mortality of 3%, but is higher if more than 200ml of imcompatible blood are administered. Reaction is usually most severe if group A red cells are administered to group O patient. The syndrome is caused by the release of the polypeptide products of complement in plasma, which causes contraction of smooth muscle and degranulation of mast cells with the release of vasoactive peptides (bradykinin and serotonin). Procoagulant substances are released from the stroma of lysed red cells. Together with antigen – antibody complexes, these initiate DIC.
The clinical features in the conscious patient include:
pain at the infusion site and along the vein;
facial burning;
chest and back pain;
fevert;
rigors and vomiting;
restlessness and duspnoea;
flushed facies;
hypotension;
oozing from vascular access sites and wounds.

Investigations
reporting to blood transfusion department
reconfirmation of belonging of blood to pt.
re- crossmatching and typing and serological
culture
electrolyte, urea and free hemoglobin
coagulation screen
discussion
The only manifestations of incompatible blood transfusion in unconscious or anaesthetized patient are sudden hypotension and bleeding due to DIC. The extensive intravascular haemolysis results in haemoglobinaemia and haemoglobinuria. Oliguria rapidly supervenes and progresses to acute renal failure. The differential diagnosis is between incompatibility and bacterially contaminated blood. The management entails:
- immediate recognition, with the cessation of transfusion and replacement of giving set;
- adequate hydration by intravenous infusion of crystalloids;
- attempts at forced diuresis, with intravenous large dose furosemide (150 mg).
If furosemide fails, a 20% solution of mannitol (100 ml) is administered. If diuresis is obtained, a high urine output (100 ml per hour) is mentained by large-volume crystalloid infusions. Often however these patients progresses to acute renal failure necessitating haemodialysis. The other problem that require immediate support is bleeding from DIC ( blood component therapy guided by clinical state and coagulation screen) and hyperkalaemia. Intravenous glucose-insulin (50 ml 50% glucose +10 units of insulin) is administered if serum potassium rises above 6.0 mmol/L. This is followed by an intravenous infusion of 10% glucose containing 10 units of insulin over a period of 4 hours. After the initial resuscitation is completed, investigation of such an incident is essential.
Acute haemolytic reactions with a similar picture may arise from acute haemolysis caused by preformed antibodies in the patient’s blood as a result of alloimmunization to minor blood group antigens in the donated unit. These may be encountered in patients requiring repeated blood transfusions. Delayed haemolytic transfusion reactions are rare but can occur in patients whose level of antibodies to the blood group antigen is so low that it escapes detection by the pretransfusion screen. Following transfusion, the secondary immune response raises the antibody titre to a level that results in the delayed destruction of the transfused cells. Thus the manifestations, which include fever, falling haemoglobin, jaundice and haemoglobiuria, appear some 5- 10 days after the transfusion. Delayed haemolytic transfusion reaction are seldom fatal.

Transfusion related acute lung injury
This is one cause of acute respiratory distress syndrome(ARDS) and was previously thought to result from pulmonary microvascular occlusion by microaggregates of platelet, leukocytes and fibrin (50 – 200 micro m), which are known to be present in stored blood. For this reason microaggregate filters were recommended for transfusions using in excess of 5 units of blood. A more definite cause is donor blood containing antibodies to the patient’s leukocytes (nearly always donations from multiparous women). Following transfusion, the patient develops fever, increasing breathlessness, non-productive cough and hypoxemia. The chest x-ray shows the typical features of ARDS, with perihilar infiltrates leading to a whiteout in severe cases.

Metabolic, haemostatic and respiratory complications
These complications are confined to the patients who, because of severe haemorrhage, receive a massive blood transfusion of stored blood. Massive blood transfusion is defined as a volume equivalent to or exceeding the patient’s own blood volume transfused within 24 hour. Apart from being cold (4 degree C), stored blood has an acid pH, contain citrate anticoagulant, has elevated plasma potassium and ammonia and reduced 2,3-DGP. The metabolic consequences therefore include the following.
- Hypothermia may lead to cardiac arrhythmias, including ventricular fibrillation and asystole. For this reason, blood warming is necessary if the transfusion rate exceeds 50 mL /min. Unfortunately heating coils increases the resistance of the giving circuit; nonetheless their use is essential in these patients.
- Acidosis.
- Increased affinity of oxyhaemoglobin for oxygen, which is thus not readily released to the tissues, thereby contributing to defective tissue oxygen uptake. However, increased oxygen affinity reverses after transfusion.
- Citrate intoxication is due to the chelation of ionized calcium, which may result in prolongation of QT interval. However this does not usually affect cardiac function and ionized calcium level rapidly return to normal after the transfusion as the excess citrate is metabolized and excreted. Thus the use of supplemental calcium is not justified, particularly as it may itself give rise to arrhythmias.
- Hyperkalaemia is seldom a problem because excess plasma K+ inters the red blood cells with warming to body temperature. However it is a consideration in patients with acidosis and renal failure when calcium is administered as the physiological antidote.
- Stored blood is deficient in platelets and labile clotting factors ( 5, 7). For this reason, massive transfusion of stored blood induces a dilution of labile clotting factors in addition to moderate thrombocytopenia. The deficiency of labile clotting factors can be circumvented by the administration of 2 units of FFP for every 8 units of blood. The transfusion-related thrombocytopenia is seldom sigmificant and can usually be ignored.

Circulatory overload
Circulatory overload is encountered in the transfusion of anaemic patients, particularly those with severe and long-standing anaemia. These patients must be transfused very slowly and only with packed cells (with or without concomitant diuretic therapy). In some patients, an exchange transfusion has to be carried out o avoid severe congestive failure.

Transfusion of bacterially contaminated/ infected bloon
This disastrous complication is fortunately rare in the UK. The majority have beed associated with platelet transfusions. The pathogens are usually cold-growing strains of Pseudomonas fluorescens or Yersinia enterocolitica. Skin organisms such as staphylococci can proliferate in platelet concentrates stored at 20- 22 degree C. the clinical picture is similar to that of ABO- incompatible blood transfusion reaction. Despite aggressive supportive therapy. The mortality is high and averages 60%.

Delayed reactions
Transmission of infectious disease
A wde spectrum of infectious disease can be transmitted by the transfusion of blood and blood products, although the modern practice of screening blood donors and heat treatment of blood protein products means the risk is extremely small. Post-transfusion levels of HIV, human T –cell leukaemia virus (HTLV), HBV and HCV are extremely low and the risk of their transmission is minimal compared with other risks. Hepatitis A can very occasionally be transmitted by blood products. Hepatitis G has been recently identified; currently, this can oonly be done by gene amplification technology and there is no screening test. It is not known whether hepatitis G can cause serious disease and whether the existing plasma fractionation and heat treatments inactivate it, though this thought likely. The other concern relates to rensmission of new variant CJD but as yet no cases have been documented.
Human parvovirus B 19 may not be inactivated by current plasma fractionation and heat treatments. It causes depressed erythropoisis in sime patients. HTLV- related disease following transfusion is extremely rare in the UK and for this reason donors ae not screened for HTLV-1 or HTLV-2 infection. However the prevalence of HTLV-1 is high in some countries, notably Japan and Caribbean. HTLV-1 causes neurological disease and a rare form of adult T- cell leukaemia, usually many years after the transfusion.
Current concern relates to infection by the prion protein responsible for new variant CJD by donors harbouring the infection but showing no sign of the disease. Cytomegalovirus is a problem because 50% of UK donors have antibody to CMV, although fortunately only a fraction of antibody positive donations transmit the virus. Post-transfusion CMV is important in premature infants born to CMV antibody negative mother and in CMV negative recipients of bone marrow allografts from CMV seronegative donors. These patients should receive CMV negative products or leukocyte depleted bliid components. The HIV problem has been largely with donor selectin and testing.

Immune suppression
There is no doubt about the immunosuppressive effect of blood transfusion; indeed prior to the introduction to the cyclosporine, transfusion before renal transplantation was employed specially to improve graft survival. The use of cyclosporine has made this procedure unnecessary. In the context of general surgery, preoperative blood transfusion has undoubted undesirable consequences because of its immunosuppressive effect ( which is additive to the immunosuppressive effect of operative trauma). Perioperative blood transfusion also increases the risk of infective complications (proven) and may increase recurrence rate and reduces disease free survival in patients extirpative surgery for cancer. Later however remains unproven.