Vox Sanguinis (2004) 87 (Suppl.

1), S74S76

ORIGINAL PAPER
Blackwell Publishing, Ltd.

ES06.02

2004 Blackwell Publishing

The bodys response to blood loss

M. A. Garrioch
Southern General Hospital and University of Glasgow, Glasgow, UK

Introduction
Maintenance of circulating blood volume is one of the most important homeostatic mechanisms that the body must support. Poor blood supply to the tissues ultimately affects every cell in the body and organ dysfunction will quickly develop if tissue perfusion fails. Haemorrhagic shock is dened as a failure of adequate tissue perfusion resulting from a loss of circulating blood volume.

Homeostatic and subcellular mechanisms

Signicant blood loss from any cause initiates a sequence of stress responses that are intended to preserve ow to vital organs and to signal cells to expend internal energy stores. Haemorrhagic shock reduces wall tension in the large intrathoracic arteries, which activates baroreceptors. Adrenergic reexes that have neural and circulating hormonal components are also activated. Neural effects are immediate; hormonal changes may be rapid, but some time is needed for them to take full effect. The two major neural components are sympathetic bres from the stellate ganglion, which stimulate the heart, and sympathetic bres from regional ganglia, which cause peripheral arterial vasoconstriction. The circulating stress hormones derive mainly from the hypothalamicpituitaryadrenomedullary axis. They lead to secretion of epinephrine and norepinephrine from the adrenal medulla and corticosteroids from the adrenal cortex, renin from the kidney, and glucagon from the pancreas. These hormones signal the liver to break down glycogen in order to release glucose into the plasma, promote release of fatty acids from adipose tissue via lipolysis, and stimulate the breakdown of tissue glycogen stores. At a cellular level, blood loss rst affects the mitochondria. Mitochondria function at the lowest oxygen tension in the body, but consume almost all the bodys supply of oxygen. More than 95% of aerobic chemical energy comes from mitochondrial combustion of fuel substrates (fats, carbohydrates, ketones) using oxygen to produce carbon dioxide (CO2) and

water. Most cellular energy transfer derives from acetyl coenzyme A (aCoA) formed by one of two pathways: oxidation or decarboxylation of pyruvate. Either fatty acids or ketones are produced by -oxidation. Pyruvate derives from either glycolysis or lactate dehydrogenation. ACoA is consumed by the tricarboxylic acid (TCA) cycle and forms reduced pyridine and avin nucleotides. These pass electrons along a series of proteins in the inner mitochondrial membrane, culminating in the reduction of molecular oxygen to form water. The mitochondrion thus harnesses energy from this process to form adenosine triphosphate from adenosine diphosphate plus inorganic phosphate. This forms the basis of all cellular energy production. In the early stage of shock, the skeletal muscle and splanchnic organs are affected more by oxygen deprivation than by a lack of delivery of fuel substrate. As a result, shock rapidly stalls transfer of electrons in the mitochondria and jams the pathways of acetyl coenzyme A input into the TCA cycle. Lactic acid results and is transported actively across the cell membrane by way of a specic protein transporter. In the resuscitated haemorrhagic shock patient, lactate production may also occur from skeletal muscle, not entirely because of low mitochondrial oxygenation, but because the delivery of pyruvate from glycolysis overwhelms the ability of dehydrogenase enzymes in the TCA cycle to dispose of pyruvate. Pyruvate is then converted into lactate, a condition known as aerobic glycolysis. Thus, it can be seen that elevated concentrations of lactate in the blood are a sentinel marker of widespread inadequate tissue perfusion. When adequate resuscitation has been achieved, lactate levels return to normal.

Global physiological effects

The physiological responses that the body mounts to increasing blood loss are well dened by the American College of Surgeons in their Advanced Trauma Life Support Education Programme [1]. These changes are observed as the percentage of blood lost reaches certain levels and are graded as different classes of haemorrhage. Important physiological parameters to aid recognition and treatment of major haemorrhage are mental status, respiratory rate, peripheral perfusion, pulse rate, blood pressure and urine output. These parameters form the basis of the four classes of haemorrhage recognized in a 70-kg adult. Cardiovascular

Correspondence: M. Garrioch, Director of Intensive Care and Senior Lecturer in Anaesthesia, Southern General Hospital, Glasgow G51 4TF, UK E-mail: magnus.garrioch@doctors.org.uk

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response to haemorrhage can vary with underlying cardiopulmonary status, age, presence of hypo- or hyperthermia and presence of ingested drugs. This should be remembered when applying this classication. This classication does not apply to small children or infants, who are more dependent on heart rate rather than blood-pressure maintenance to compensate for blood loss. A fall in blood pressure in a child is a preterminal event.

has dropped to be, in some cases, unrecordable, and the pulse is barely palpable. Vital organ perfusion is failing.

Other guides to recognition of haemorrhagic shock

Not all haemorrhagic shock is as obvious as the ATLS classication would suggest. A change in arterial acidbase status will often precede any signicant decrease in cardiac output with haemorrhage. The arterial and venous blood bicarbonate level and base decit will decrease early in haemorrhage even if pH and blood pressure remain in the normal range [2]. Distinguishing simple haemorrhage from haemorrhagic shock is possible by noting that when the base decit becomes pathologically low, widespread tissue hypoperfusion may be suspected. Patients with tachycardia, a low base decit, and low urine output should be suspected of having haemorrhagic shock. The base decit is dened as the amount of strong base that would have to be added to a litre of blood to normalize the pH. In the clinical setting the base decit is indirectly calculated from the pH and arterial CO2 partial pressure (PaCO2) and is normally higher than 2 mM. The brainstem chemoreceptor responds to acidaemia by increasing respiratory rate, leading to reduced PaCO2. After approximately one-third of the total blood volume is acutely lost, cardiovascular reexes can no longer cause adequate lling of the arterial tree, and hypotension supervenes. Arterial hypotension is generally dened as an arterial blood pressure below 90 mmHg, but this threshold should be increased to 100 mmHg in patients with known systemic hypertension and in patients over age 60 years. With the development of hypotension, the patient can no longer hyperventilate sufciently to maintain a normal arterial pH, and acidaemia occurs. Blood gases can therefore provide very useful information regarding the early detection of acute blood loss.

Class I haemorrhage (015% total blood volume)

This represents up to 750 ml blood loss. Minimal physiological changes occur at this level. A patient may exhibit mild anxiety, but heart rate, blood pressure and peripheral circulation largely remain unchanged. Urine output is only slightly decreased. The body can compensate well for this degree of haemorrhage. This situation is mimicked by a blood donation.

Class II haemorrhage (1530% total blood volume)

Beyond 750 ml blood lost, sympathetic nerve stimulation occurs as described above. A modest elevation in heart rate and a decrease in the pulse pressure, as the diastolic pressure rises, are to be expected. A degree of peripheral shut down, i.e. cool extremities and digital cyanosis, accompanied by pallor, occur. Inexperienced staff may fail to recognize the diastolic pressure rise associated with increasing blood loss. A blood pressure of 120/70 changing to a pressure of 120/95 may be a sign of the impending cardiovascular collapse associated with a blood loss in excess of 1500 ml. This physiological change is a direct result of the vasoconstriction induced by sympathetic nerve stimulation of the vascular tree. Hyperventilation to a respiratory rate of over 20 breaths/min can also be expected at this stage as the tissues are starting to suffer a lack of oxygenation and increasing production of lactic acid stimulates the respiratory centre.

Class III haemorrhage (3040% total blood volume)

Now haemorrhagic shock is well established and a critical phase is reached, with a drop in systolic and diastolic blood pressure. Mental confusion and anxiety are normal, respiratory rate is high, peripheral perfusion is very poor, and the patient appears pale and diaphoretic. The pulse rate is invariably well over 100 beats/min and the production of urine is negligible. Under these circumstances, widespread failure of tissue oxygenation is occurring, with diversion of what blood ow there is to essential organs such as brain, kidney and heart.

Treatment of haemorrhagic shock

Conventional wisdom regarding shock has been directed at rapid correction of the source of haemorrhage and rapid restoration of normal circulating blood volume and perfusion. The ATLS curriculum advocates the immediate establishment of large-bore intravenous access and infusion of resuscitative uids, characteristically up to 2 l of Hartmanns solution, followed by blood. The goal is to return the blood pressure to normal. If blood pressure subsequently falls again, this is taken as a sign of serious injury, which must be addressed by immediate surgery. Maintenance of blood pressure during the period of active haemorrhage is presumed to reduce the risk of organ-system failure and irreversible shock. This approach may not be as sensible as it seems. The analogy of pouring water into a bucket with a hole at the bottom

Class IV haemorrhage (over 40% of blood volume)

This situation is immediately life-threatening and within 15 min a mortality of 50% is to be expected. Blood pressure

2004 Blackwell Publishing Ltd. Vox Sanguinis (2004) 87 (Suppl. 1), S74S76

76 M. Garrioch

can be made. The greater the volume of water added to the bucket, the more rapidly it runs from the hole. In the traumatized patient, this means greater blood loss, a longer duration of bleeding, and disruption of the normal plasma composition including dilution of clotting factors. Aggressive uid administration and higher blood pressure potentially increase the extent of haemorrhage. Surgical control must be rapidly achieved. What is not understood at the present is the priority that must be given to these two conicting goals: maintenance of perfusion and limitation of haemorrhage. Deliberate hypotension is employed in elective head and neck surgery, prostate resections, and major orthopaedic procedures as a means of reducing the blood loss and need for transfusion. Trauma patients, however, may have already lost a substantial amount of blood before hospital arrival and be in some degree of shock. Identifying the optimal balance between uid resuscitation and haemorrhage control is one of the most difcult and controversial areas in trauma care today. Delayed or limited resuscitation until surgical control is available may improve outcome [3].

The effects of persisting inadequate circulating volume

Untreated or inadequately treated haemorrhagic shock will ultimately have serious consequences for the patient. Lifethreatening problems can occur a considerable time after the traumatic event. With limited or inadequate restoration of circulating volume, initiation of inammatory changes can be expected. Shock causes neutrophil activation and liberation of adhesion molecules, which promote binding of neutrophils to lung and vascular endothelium. Within the lung, this initiates capillary leak that can produce the adult respiratory distress syndrome. Within the circulation, inammatory cytokines are liberated during resuscitation, and membrane injury occurs in many cells. In the liver, damage from inammation and reactive oxygen species from neutrophils is compounded by persistent microischaemia. During resuscitation from haemorrhagic shock, the normal balance of vasodilatation by nitric oxide versus vasoconstriction by endothelins becomes distorted, producing patchy centrilobular ischaemic damage in the liver, which may produce an immediate rise in blood transaminase levels. A growing body of evidence suggests that re-transfusion from haemorrhage exerts greater injury to the heart than the actual hypotensive insult [4]. Depending on the degree of hypotensive insult, the kidney may manifest acute spasm of the preglomerular arterioles, causing acute tubular necrosis. Systemic metabolic changes can impair fuel delivery to the heart and brain, secondary to depressed hepatic glucose output, impaired hepatic ketone production, and inhibited peripheral lipolysis.

Activated, sticky neutrophils can also directly damage organs by liberating toxic reactive oxygen species, N-chloramines, and proteolytic enzymes. Neutrophils can also plug capillaries and cause microischaemia. Although much of the knowledge about the inammatory responses in shock has evolved from the study of septic shock, the consensus is that any low-perfusion state that produces widespread cellular hypoxia can trigger systemic inammation. Haemorrhagic shock is one such low-ow state. Multiple tissues (e.g. macrophages, endothelial and epithelial cells, muscle cells) are signalled to enhance transcription of messenger ribonucleic acid (mRNA) coding for cytokines, including tumour necrosis factors (TNF-, TNF-) and interleukins (IL-1, IL-6). The effects of intravascular cytokine release on the body are manifest as systemic inammatory response syndrome (SIRS) [5]. SIRS can progress to sepsis syndrome and ultimately septic shock. One additional mechanism by which this is suggested to occur is a breakdown in the integrity of the gut mucosa caused by inadequate perfusion of the gut wall. This leads to bacterial translocation of Gram-negative gut bacteria into the bloodstream, thus inducing cytokine release and septic shock. The prevention of inadequate circulation by the timely surgical intervention and restoration of circulating volume will ameliorate the above pathological processes.

Conclusions
The consequences of inadequate circulating blood volume are life-threatening. Recognition of haemorrhage by the classical physiological signs is important for clinicians to diagnose shock and prevent both short- and long-term complications of this condition. These interventions centre on surgical control of bleeding and rapid restoration of blood volume.

References
1 Committee on Trauma, American College of Surgeons: Advanced Trauma Life Support Program for Physicians. Chicago: American College of Surgeons, 1999 2 Davis JW, Kaups KL, Parks SN: Base decit is superior to pH in evaluating clearance of acidosis after traumatic shock. J Trauma 1998; 44:114 118 3 Bickell WH, Wall MJ, Pepe PE, Martin RR, Ginger VF, Allen MK, Mattox KL: Immediate versus delayed resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331:1105 1109 4 Maitra SR, Gestring M, el-Maghrabi MR: Alterations in hepatic 6phosphofructo-2-kinase/fructose-2,6-bisphosphatase and glucose6-phosphatase gene expression after haemorrhagic hypotension and resuscitation. Shock 1998; 8:385 388 (erratum 9:78) 5 Bone RC, Grodzin CJ, Balk RA: Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997; 112:235 243

2004 Blackwell Publishing Ltd. Vox Sanguinis (2004) 87 (Suppl. 1), S74S76