Hypoperfusion is a deficiency of blood passing through an organ or body part.

Goals of fluid replacement

Vital organ perfusion, in particular, to the brain, the heart, and the kidneys is one of the goals in keeping a balanced intravascular water compartment and avoiding the leakage to a dead third space. Also, intestinal perfusion seems to be important because an intraoperative study using gastric tonometry indicated that low perfusion was a risk factor for an exacerbated inflammatory response [11]. Therefore, hypovolemia should be avoided in the surgical patient and seems to be a major concern among anesthesiologists and surgeons. On the other hand, Evans demonstrated more than 100 years ago that there was a straight relationship between high infusion of saline solutions and complications [12]. Unfortunately, the negative impact of fluid overload on surgical patients seems not to be so much valued by physicians as hypovolemia is. In fact, the common belief is that the patient will soon recover his/her balance without any compromised organ when excess fluids are infused.

Contrary to this belief, various studies have pointed out that hyperhydration leads to increased length of hospital stay, morbidity, and mortality. Lobo et al. assessed patients undergoing open colectomies and showed that a positive fluid and sodium balance increased the patient’s body weight by an average of 3 kg, and this was directly associated with increased postoperative dysmotility and length of hospital stay [5]. Other authors reported similar results when comparing patients with volume restriction with liberal infusion of perioperative fluid therapy. Those with better fluid control had less weight gain, passed flatus faster (3 vs. 4 days), and eliminated stools earlier (4 vs. 6 days). Also, the length of stay was decreased in the fluid controlled group [13]. A recent randomized study with patients undergoing laparoscopic cholecystectomies, an operation that usually lasts 60 minutes, showed a significant weight gain and an increase in extracellular water, especially in patients who further received postoperative intravenous solutions. The study indicated no need to prescribe any postoperative fluids for patients undergoing laparoscopic cholecystectomies that were also related to higher nursing time and increased costs [14].

In conclusion, fluid replacement should mandatorily be tailored for each patient according to the clinical condition and never based on “one treatment fits all”.

Essential principles and semiquantitative relationships

In most organs, perfusion pressure equals the difference between inlet (arterial) and outlet (venous) pressures. Intracranial outlet pressure differs in this respect from central venous pressure or cerebral venous sinus pressure, as the brain is surrounded by a rigid skull. Intracranial venous pressure is coupled to intracranial pressure (ICP). Therefore, cerebral perfusion pressure (CPP) is defined as follows (Miller et al., 1972):

MeanCPP=meanarterialpressure–meanICP

One might expect that a rise in ICP would impede blood flow and cause ischemia. However, this is not the case, assuming autoregulation of cerebral blood flow (CBF) works correctly.

ICP is a complex modality derived from volumetric changes of intracranial blood, cerebrospinal fluid (CSF), brain parenchyma plus, in pathologic states, space-occupying lesions. Classically, the Monro–Kellie doctrine states that the sum of all intracranial volumes must remain constant. This is probably not 100% accurate, as the volume of the dural sac in the lumbar channel may expand slightly against internal vertebral venous plexuses.

ICP has dynamic (changing in time) and static (which may also change over time, but at a much slower rate) components. Both fast and slow changes in ICP are associated with a change of volume of arterial and venous blood, CSF, and brain tissue (edema formation) or other volume/space-occupying lesions (e.g., hematomas, tumors, or abscesses). It is important to distinguish between different components of ICP, as optimal clinical strategies to combat intracranial hypertension depend on which component is elevated. For example, arterial blood volume may raise ICP to very high levels in a matter of minutes and these elevations are known as plateau waves, which are secondary to massive, intrinsic arterial dilatation. Rapid, short-term hyperventilation usually reduces ICP in such cases. The CSF-circulatory component may elevate ICP in a scenario of acute hydrocephalus. In such cases, extraventricular drainage is particularly helpful. Venous outflow obstruction may also elevate ICP, and proper head positioning or investigation of possible venous thrombosis may be crucial. Finally, if ICP is elevated due to brain edema or a space-occupying lesion, osmotherapy or surgical intervention (including decompressive craniectomy) may be especially beneficial.

Dynamic components of ICP are mainly derived from the circulation of cerebral blood and CSF (the mathematic operator in the formula below should not be represented by a simple sum, therefore the generic symbol # is used):

ICP=ICPvascular#ICPCSF

The vascular component is difficult to express quantitatively. It is probably derived from the pulsation of the cerebral blood volume (CBV) detected and averaged by nonlinear mechanisms of regulation of cerebral blood and CSF volumes. More generally, multiple variables such as the arterial pressure, state of autoregulation, and cerebral venous outflow all contribute to the vascular component.

The CSF-circulatory component may be expressed using Davson's equation (Davson et al., 1970):

ICPCSF =resistancetoCSFoutflow *CSFformation+pressureinsagittalsinus

Any factor which, under physiologic (e.g., compression of jugular veins) or pathologic conditions (e.g., brain swelling, space-occupying lesion, or obstruction of CSF absorption) disturbs CSF circulation, may provoke an increase in ICP according to this formula.

Clinical Presentation

Systemic cardiac output and organ perfusion can be severely compromised in these patients. Systemic or suprasystemic RV pressures can result in a leftward shift of the interventicular septum (known as ventricular interdependence) that pancakes the LV and further reduces the compliance and filling of the already small LV; a secondary effect of these alterations is to reduce R-L flow across the atrial septum (because the impedance to LA emptying has increased). There is also likely to be RV afterload mismatch, resulting in RV distention and tricuspid regurgitation. Thus, systemic cardiac output largely depends on a physiologic R-L shunt across the ductus arteriosus, but one that is supplied by a failing RV. These patients have a small heart and congested lungs on chest radiograph, the latter appearing worse in the case of obstructed TAPVR. The diagnosis is usually confirmed by surface echocardiography.

Patients with TAPVR are hypoxemic because of complete mixing; their degree of hypoxemia is further exacerbated by low cardiac output (which reduces mixed venous oxyhemoglobin saturation [Svo2] and hence the Sao2 that results from complete mixing), pulmonary edema (which causes intrapulmonary shunt and V/Q mismatch, leading to low pulmonary venous oxyhemoglobin saturation [Spvo2]), and reduced PBF arising from increased PVR. Efforts to increase pulmonary blood flow in these patients will only worsen the pulmonary edema (thus, e.g., inhaled nitric oxide [iNO], as well as other inhaled pulmonary vasodilators, are clearly contraindicated).

Patients with obstructed TAPVR present at birth with hypoxemia and poor systemic perfusion. In many, there is an ongoing metabolic acidosis and evidence of end-organ (hepatic and renal) dysfunction. In patients with severe pulmonary venous obstruction leading to suprasystemic RV and PA pressures and R-L shunting across the ductus arteriosus, ductal patency is necessary to maintain cardiac output (i.e., use of PGE1 for temporary palliation may be indicated); frequently, inotropic support is required. In patients with less severe obstruction and subsystemic RV and PA pressures, ductal flow will be bidirectional or L-R. In these patients, ductal patency may exacerbate pulmonary edema.

History of Machine Perfusion in Solid Organ Transplantation

The concept of isolated organ perfusion is older than transplantation itself. In the early to mid 1900s, normothermic perfusion was studied as a way of sustaining the function of organs in isolation, both in situ15-18 and outside the body.19-23 When clinical transplantation activity began in the 1960s, however, interest turned from normothermic to hypothermic methods for maintaining organs, in particular the kidney. Continuous perfusion with cooled, oxygenated blood or plasma was initially the most successful form of extracorporeal renal maintenance.24-29

During subsequent years, however, machine perfusion in organ preservation gradually fell out of favor. Although the first human liver transplants were performed using grafts arising from DCD donors, the Ad Hoc Committee of Harvard Medical School produced the definition of irreversible coma in 1968, making it possible for the first time to recover organs from donation after neurological determination of death (DND) donors with intact circulation at the time of donation.30 Given the fact that organs recovered from DND donors had not suffered warm ischemic injury and generally functioned better than those recovered from DCD donors, organ maintenance via extracorporeal machine perfusion became less of a necessity. Solutions for static cold storage also underwent dramatic improvements in terms of composition and ability to preserve organs in an adequate state of viability for periods of 24 hours and longer,31-34 and studies performed in the 1970s and 1980s indicated that there was little to no added benefit for machine perfusion over static storage in cold solution.35,36

Over the past two decades, however, donors have become progressively older and less healthy in general.37 Given an improved ability to take care of patients with traumatic brain injury, fewer donors may be declared dead based on neurological criteria.38 Instead, many more now have life support intentionally removed to provoke cardiac arrest, converting what was a relatively orderly process of organ donation into a rush to cool down the organs as quickly as possible using the so-called super-rapid recovery technique.39 And in spite of our best efforts to limit ischemic injury in these grafts, we nonetheless continue to fail to adequately maintain their viability using the means of preservation most readily available to us. Allograft dysfunction leads to increased transplantation costs and significantly higher rates of recipient morbidity and mortality and has been recognized as a major problem associated with the use of marginal livers. Taking the aforementioned facts into account, as well as the fact that preservation technology has advanced considerably in recent years and smaller, more portable machines have been developed, it is no surprise that machine perfusion in solid organ transplantation is once again at the forefront.

Hemodynamic Management

Hemodynamic management should maintain adequate organ perfusion and arterial pressure without fluid overload or excessive vasoconstriction and should preserve the possibility of cardiac donation. Reasonable hemodynamic goals include a mean arterial pressure above 65 mmHg, a heart rate of 100 or less, and central venous pressure of 8 mmHg. Some inotropic support (with pressor activity) is usually required. Norepinephrine (usually less than 0.1 μg/kg/min) is widely used for this purpose. After an acceptable mean arterial pressure has been obtained, the hemodynamic response to a volume challenge should be assessed. Dopamine may produce an unwanted polyuria and epinephrine unwanted metabolic effects (see Chapter 3). Low-dose vasopressin (0.5 to 1 unit/hr; compare this to the dosage used to treat vasoplegic shock, described in Chapter 3) is effective in reducing catecholamine requirements17,18 without apparent detriment to subsequently transplanted organs,17 and it should be used after adequate volume loading if catecholamine requirements are high.

Hypovolemia and hemoconcentration should be corrected with resuscitation fluids.19 Crystalloid infusion may worsen pulmonary function20 and somewhat larger volumes (1.3 times more21) may be required than if colloid is used. The effects of hydroxyethylstarch on subsequent kidney graft function are debated,22,23 but moderate volumes are commonly given. Anemia is well tolerated in brain death, but red blood cells may be given to maintain the hematocrit at about 0.25, pending organ retrieval. Hyperosmolarity (>310 mOsm/l, corresponding to serum sodium >155 mmol/l) should be prevented by the administration of free water (1 to 2 ml/kg/hr as 5% dextrose) because severe donor hyperosmolality is associated with poor liver graft function.

Definition

Shock is a state of inadequate organ perfusion (oxygen deficiency) sufficient adversely to affect cellular metabolism, causing the release of enzymes and vasoactive substances,7 i.e. it is a low flow or hypoperfusion state.

Typically the blood pressure is low, reflecting reduced cardiac output. The exception is septic shock, where the cardiac output is typically high, but it is maldistributed (due to constriction, dilatation, shunting), leading to poor oxygen utilisation and tissue injury (warm shock).

The essential element, hypoperfusion of vital organs, is present whatever the cause, whether pump failure (myocardial infarction), maldistribution of blood (septic shock) or loss of intravascular volume (bleeding or increased permeability of vessels damaged by bacterial cell products, burns or anoxia). Functions of vital organs, such as the brain (consciousness), lungs (gas exchange) and kidney (urine formation) are clinical indicators of adequacy of perfusion of these organs.

Normothermic Oxygenated Perfusion

NOP has the advantage of physiological organ perfusion that is close to the in situ situation. This method, which uses supplemented blood as perfusate, allows real-time assessment of viable liver function by measuring oxygen consumption, bile flow, and urea synthesis.122-125 A significant advantage is that the perfused organ may be maintained for an extended period of time. One experimental study using porcine livers showed that NOP maintained the organ viability for up to 72 hours of extracorporeal perfusion.122 In another experimental model, NOP rescued porcine liver grafts subjected to 60 minutes of warm ischemia, whereas nonperfused livers resulted in nonfunction and recipient death after transplantation.124 In a more recently published study, NOP proved to be superior to cold storage in porcine DCD livers in terms of liver injury, synthetic graft function, cytokine and proinflammatory response, and survival.126 Another advantage of NOP is related to the group of steatotic donor livers. Two experimental studies demonstrated that NOP caused defatting of steatotic livers and metabolic conditioning.127,128 The concept of in situ NOP has been tested in one clinical study only.129 Donors with irreversible cardiac arrest before donation (DCD) were maintained with normothermic extracorporeal membrane oxygenation until potential organ procurement. Ten of 40 patients treated under this protocol donated their liver for transplantation. In this series one allograft developed primary nonfunction and another hepatic artery thrombosis. The other remaining livers displayed reasonable postoperative graft function. Despite the benefits of NOP, this approach seems to lose its protection when cold preservation is employed.130,131

Cardiovascular

Hypotension due to nitroprusside can cause reduced organ perfusion and circulatory steal, which in one case resulted in renal impairment [18]. Coronary steal has been reported in patients with myocardial ischemia [19].

The hypotension that sodium nitroprusside causes results in a reflex tachycardia, which can be prevented by beta-blockade without a significant change in mean arterial pressure [20].

In 10 healthy volunteers local skin hyperemia induced by nitroprusside iontophoresis was significantly increased by sildenafil 100 mg but not 50 mg without changing the incidence of headache [21]. There was one episode of symptomatic arterial hypotension in one case after the administration of sildenafil 50 mg 30 minutes after the administration of nitroprusside. The authors suggested that the combination of a phosphodiesterase type 5 inhibitor and nitrates given by skin iontophoresis could be beneficial in the management of conditions such as severe Raynaud's phenomenon.

12 What are the four main advances in burn care that have dramatically reduced mortality over the last 50 years?

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Appropriate resuscitation: Restoration of end-organ perfusion while avoiding overresuscitation.

Control of infection: Application of topical antimicrobial agents to prevent wound infections and using systemic antimicrobials only after documentation of invasive wound infection (cellulitis), not colonization, and presence of systemic infection (bacteremia).

Modulation of hypermetabolism: Early and appropriate nutrition, anabolic agents, early occupational and physical therapy.

Early excision and grafting: Protein catabolism progressively worsens with the presence of third-degree thermal injury. The goal is to remove all nonviable tissue within 96 hours to lessen the degree of catabolism.

11 What therapies should be considered immediately in a patient with hypotension and evidence of inadequate vital organ function?

Fluid and vasopressor therapy can rapidly restore vital organ perfusion, depending on the cause of the deterioration. In most patients, a fluid challenge is well tolerated, although it is possible to precipitate heart failure and pulmonary edema in a volume-overloaded patient. Other therapies that may be immediately lifesaving include thrombolysis or coronary angioplasty for an acute myocardial infarction. Patients with hypotension from sepsis may benefit from early therapy involving defined goals for blood pressure, central venous pressure, central venous oxygen saturation, and hematocrit.

Rivers E, Nguyen B, Havstad S, et al: Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med 345:1368–1377, 2001.