The Conduction System in the Heart


INTRODUCTION  
The conduction system in the heart is an intrinsic system whereby the cardiac muscle is automatically stimulated to contract, without the need for external stimulation (Waugh & Grant, 2007). It comprises specialised cardiac cells, which initiate and conduct impulses, providing a stimulus for myocardial contraction. It is controlled by the autonomic nervous system; the sympathetic nerves increase heart rate, contractility, automaticity and atrioventricular (AV) conduction, while the parasympathetic nerves have an opposite effect.

Blood Transfusion and Its Components




E. Celis-Rodriguez, K. Reinhart, Y. Sakr
Introduction

tRANSFUSSION
Transfusion of blood products in the critical care setting is a common practice that has been performed for many years. Since the 19th century, when James Blundell reported the clinical application of the treatment of hemorrhage for the first time in the Lancet [1], blood transfusion has been the cornerstone in the treatment of severe hemorrhage, not only as a means of improving oxygen transport capacity, but also to maintain homeostasis and reduce mortality rates [1]. The 10/30 rule was the standard of care for decades [2], but the first report of this appeared in the 1940s, when Lundy et al. [3] stated that “It is a clever idea to provide blood before surgery,” referring to patients whose hemoglobin levels were between 8 and 10 g/dL. With the more restrictive use of blood transfusion since the 1980s, there have been attempts to define specific indications for transfusion, minimal hemoglobin levels for critically ill patients, and the benefits and potential risks of transfusion [4].

The Neuroendocrine Response to Sepsis


Introduction
Acute response to LPS includes the release of a number of proinflammatory mediators that reach the brain in areas free of blood-brain barrier, or via specific transport systems. The hypothalamic-pituitary axis is also activated via neural routes. Then, infection is characterized by high circulating levels of adrenocorticotrope hormone (ACTH), and cortisol which remain in plateau as long as the stressful condition is maintained. Circulating vasopressin levels follow a biphasic response with high concentrations, followed by relative vasopressin insufficiency in about one third of cases.

nursing care plan for STATUS ASTHMATICUS



Status asthmaticus is a critical emergency that requires prompt intervention to avoid acute and possibly fatal, respiratory failure. In this condition, the asthmatic attacks are unresponsive to medical therapeutics, with severe bronchospasms creating decreased oxygenation and perfusion. During an acute asthmatic attack, the individual may demonstrate varying degrees of respiratory distress depending on the duration of the attack, and the severity of spasm.

Critical Nursing Care Plan For: PNEUMOTHORAX



A pneumothorax occurs when free air accumulates in the pleural cavity between the visceral and parietal areas, and causes a portion or the complete lung to collapse. Pressure in the pleural space is normally less than that of atmospheric pressure but following a penetration injury, air can enter the cavity from the outside changing the pressure within the lung cavity and causing it to collapse.

CRITICAL NURSING CARE PLAN FOR: Pneumonia



Pneumonia is an acute infection of the lung's terminal alveolar spaces and/or the interstitial tissues which results in gas exchange problems. The major challenge is identification of the source of the infection. Pneumonia ranks as the sixth most common cause of death in the United States.

CRITICAL NURSING CARE PLAN FOR PULMONARY EMBOLISM



A pulmonary embolus (PE) usually results after a deep vein thrombus partially or totally dislodges from the pelvis, thigh, or calf. The clot then lodges in one or more of the pulmonary arteries and obstructs forward blood flow and oxygen supply to the lung parenchyma.

Chronic Obstructive Pulmonary Disease (COPD)



Chronic obstructive pulmonary disease (COPD) is irreversible condition in which airways become obstructed and resistance to air flow is increased during expiration when airways collapse. COPD is usually further subdivided into other diseases such as bronchitis and emphysema, and actually COPD refers to these simultaneous disease entities.

Nursing Research: (Dorothy) Johnson’s Behavioral System Model

Johnson’s Behavioral System model consists of two major components, nursing and person. Nursing is a function of actions and goals while person is described as a behavioral system (Johnson, D. E., 1980). 

Nursing Research: Infection Control

The infectious process depends on the interaction between an infectious agent, a susceptible host, and the environment. Essential to this interaction is a means of transmission of the agent from an infected host to a susceptible host. This occurs through direct contact, airborne droplet transmission, and indirect contact. 

Nursing Research: Infant Injury

Injuries are defined in two ways: (a) the physical damage to the body caused by the transfer of mechanical, chemical, or thermal energy (e.g., a broken bone, salicylate-related poisoning, or frostbite to a toe); and (b) as the event that caused the damage (e.g., motor vehicle crash, aspirin ingestion, or prolonged exposure to cold). 

Nursig Research: Individual Nursing Therapy

Nursing practice is becoming increasingly complex and diverse, and many changes have been noted by authors in psychiatric mental health nursing in recent years (Jones, 2003). Increasingly, mental health services are taking place in the community rather than in inpatient settings. 

Nursing Research: Informed Consent

Informed consent is the process by which a potential subject or a legal representative is given explanations about the purpose of the research and the risks, inconveniences, costs, potential benefits, and right to withdraw from the study without repercussions. This must occur prior to obtaining written or verbal consent for enrollment. The use of in-formed consent for research and the process for obtaining it have evolved over the past 50 years. 

Nursing Research: Job Satisfaction

Job satisfaction is the degree to which individuals like their jobs. As a general attitudinal construct, job satisfaction reflects a positive affective orientation toward work and the organization, whereas job dissatisfaction reflects a negative affective orientation. Job satisfaction has been studied extensively in nursing, psychology,

Nursing Research: Job Stress

Results of a 1995 survey conducted by the American Nurses Association indicated that nurses considered stress to be their number one occupational hazard. The nursing literature is replete with opinion articles on factors in the work setting that make situations conductive to stress for nurses; however, few articles report research results. It was during the 1970s that nurse researchers as well as sociologists and psychologists became interested in studying job stress for nurses. Early research on job stress for nurses centered on the disruptive effects of changing shifts on circadian rhythms and subjective sense of well-being.

Nursing Research: (Imogene) King’s Conceptual System and Theory of Goal Attainment

Imogene King’s initial interest in theory was to develop a conceptual frame of reference to focus and organize nursing knowledge with the goal of identifying a systems theory for nursing (King, 1981). Introduced in 1981, King’s theory focused on individuals as personal systems, two or more individuals as interpersonal systems, and organized boundary systems that regulate roles, behaviors, values, and roles as social systems.

Nursing Research: Kangaroo Care

Most nurses working in an intensive care nursery have witnessed parents expressing in-tense need to hold their ill preterm infants. A new method of care addressing this need is “kangaroo care,” a term derived from its similarity to the way marsupials mother their immature young. During kangaroo care (KC), mothers simply hold their diaper-clad infant underneath their clothing, skin-to-skin, and upright between their breasts; if

Nursing Research: Leininger’s Theory of Culture Care Diversity and Universality

The Theory of Culture Care Diversity and Universality is derived from the disciplines of nursing and anthropology. Madeline Leininger conceptualized the theory in the mid-1950s while working as a clinical nurse specialist with disturbed children and their

Nursing Research: Maternal Anxiety and Adaptation During Pregnancy

Pregnancy, as a period of substantial biological and psychosocial change, can be expected to raise anxiety about the future. Anxiety is the psychological consequence of exposure to stressful circumstances that challenge one’s capacity to cope. Patterns of maternal anxiety may be adaptive or maladaptive from psychosocial and psychophysiological perspectives. Maladaptive psychosocial prenatal responses have been associated with post partal maternal adaptive difficulty, marital disturbance, and infant and childhood development problems.

Nursing Research: Measurement and Scales

The focus of measurement is the quantification of a characteristic or attribute of a person, object, or event. Measurement provides for a consistent and meaningful interpretation of the nature of an attribute when the same measurement process or instrument is used. The results of measurement are usually expressed in the form of 

Nursing Research: Medications in Older Persons

Due to increased life expectancy, older age is associated with the prevalence of multiple comorbidities (e.g., congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus), which often necessitate life-long and multiple medication intake. Consequently, older persons are the largest consumers of medication.

Nursing Care Plan In Pain


Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage (Merskey & Bogduk, 1994). It is the most common reason for seeking health care. It occurs with many disorders, diagnostic tests, and treatments. It disables and distresses more people than any single disease. Since nurses spend more time with the patient in pain than do other health care providers, nurses need to understand the pathophysiology of pain, the physiologic and psychological consequences of acute and chronic pain, and the methods used to treat pain. Nurses encounter patients in pain in a variety of settings, including acute care, outpatient, and long-term care settings, as well as in the home. Thus, they must have the knowledge and skills to assess pain, to implement pain relief strategies, and to evaluate the effectiveness of these strategies, regardless of setting.

NURSING RESEARCH: Mental Health in Public Sector Primary Care

Primary care was first comprehensively defined by the World Health Assembly following a seminal conference in Alma-Ata in 1977 (Health for All by the Year 2000). Building upon the key aspects of Alma-Ata, the 1978World Health Organization emphasized the defining aspects of primary care as essential, first-level health care embedded in the community, available to all, evidence-based, socially acceptable, and

Nursing Research: Mental Health Services Research

Mental Health Services Research (MHSR) is a relatively new, evolving area of health services research that focuses on access to, costs of, and quality of mental health care services within diverse health care delivery systems and socio-politico-cultural contexts (National Institute of Mental Health [NIMH],2003). The importance of MHSR to inform improvements to public health services has become increasingly recognized in recent

Nursing Research: Mental Status Measurement: The Mini-Mental State Examination

Individualized assessment of cognitive status is necessary for the planning and evaluation of nursing care to determine the patient’s capacity to understand instructions, be an active participant in his/her care, make health care decisions, and detect changes that will determine subsequent nursing actions. It is especially important to assess the cognitive status of elders who may have an undetected mild cognitive impairment or delirium; for example, assessing baseline cognitive status of hospitalized elders would allow early detection of side effects from receiving a new medication or of

Nursing Research : Mentoring

A formal definition of mentoring is a spontaneous pairing by two individuals or a grouping of two or more individuals who feel they can assist each other in professional and sometimes personal growth. The mentor–mentee relationship tends to evolve and endure for the rest of one’s career and consists of counseling, teaching, networking, and coaching. Vance and Olson (1998) described mentoring as a developmental and caring support or connection between two people which assists with socialization at each stage of a mentee’s career.

Nursing Research: Immigrant Women


Immigration is a process of movement of people from one country to another. Immigrants experience a transition that begins with preparation for immigration and includes the act of immigrating, the process of settling in, and over time, identity

Hemodynamic Monitoring

Hemodynamic monitoring is the use of advanced technology and application of physio-logical principles to clinically assess the cardiac function and circulatory system in critically ill patients. The pulmonary artery catheter was first introduced in 1970 by Dr. Jeremy Swan (Swan et al., 1970), and continues to be a frequently used tool in the critical care setting. The catheter tip is positioned in the distal pulmonary artery and is used to monitor pulmonary artery systolic, diastolic, and mean pressures, and to obtain blood samples to determine mixed venous oxygenation. The distal balloon port is used to measure the pulmonary artery wedge pressure (PAWP)when the balloon port is inflated with 1.5 cc of air. 

Nursing Research: Henderson’s Model

Since 1960 when the International Council of Nurses (ICN) first published Basic Principles of Nursing Care, a work their Nursing Service Committee commissioned, Virginia Henderson’s description of nursing and the unique function of the nurse has been used throughout the world to standardize nursing practice.

Homelessness

The phenomenon of homelessness is multidimensional with macro (health policy), meso (health care systems), and micro (individual) structural mechanisms. Homelessness is not a random event that occurs to families and individuals outside the context of their lives and personal history. Epidemiological medicine and social researchers continue to amass a body of literature whose focus is the identification and description of individual risk factors that are correlated with homelessness.

Hermeneutics

Historically, hermeneutics described the art or theory of interpretation (predominantly that of texts) and was prevalent in disciplines such as theology and law. German philosopher Wilhelm Dilthey (1833–1911) redefined hermeneutics as a science of historical under-standing and sought a method for deriving objectively valid interpretations. Martin Heidegger (1889–1976) recast hermeneutics from being based on the interpretation of historical consciousness to revealing the temporality of self-understandings (Palmer, R.,1969).

Home Health Systems

Home health systems are computer-based information systems designed to support care of the sick in the home. Home health systems primarily support home health and hospice programs provided by home health agencies (HHAs). Home health is more than “care in the home.” It focuses on the continuity of care from the hospital to the community, public health concepts of disease prevention and health promotion, and out-of-hospital acute illness services. 

Nursing Research in Health Indicators

Health indicators are defined as the means by which one can describe either quantitatively or qualitatively an individual’s state of health or those factors that influence the health of a health system, population, or community (Atlas of Canada, 2001). Health indicators are “constructs of public health surveillance that define a measure of health (i.e., health status or other risk factor) among a specified population” (Lengerich, 1999).

Homeless Health

Ongoing armed conflicts and poor economic conditions are daily increasing the ranks of the homeless in the world through the creation of refugees and immigrants. The level of increase in the homeless population worldwide can only be estimated because of the continuous fluctuation of this population. However, the World Health Organization as well as nongovernmental agencies managing the homeless around the world confirm that there are greater numbers each year.

Plasma Volume Expansion: The Current Controversy


Introduction
Although rapid and adequate administration of fluid is largely accepted as a mainstay of resuscitation in the critically ill patient, there is still an ongoing debate on the merits of colloids against crystalloids as first line plasma expanders. The underlying biologic rationale calls for rapid restoration of fluid losses to maintain circulating blood volume and organ perfusion.
The main arguments in favor of colloids are that they restore hemodynamic parameters faster and with less volume load than crystalloids, remain in the intravascular space longer, and lead to less pulmonary and tissue edema. An increased volume load or positive fluid balance may favor tissue edema and decrease survival. However, recent studies in patients with capillary leak syndrome have shown that extravascular lung water or pulmonary SOFA score were not influenced by type of colloid or crystalloid fluid administered [1,2]. Moreover, colloids have beneficial effects on microcirculation and rheology, and exert potential anti-inflammatory effects. In comparison to albumin, synthetic colloids are less costly.
Crystalloid supporters argue that crystalloids are safe, do not interfere with coagulation beyond the effect of hemodilution, are not taken up and stored in the body, and are inexpensive to use.
Until recently, available information was based on comparison of fluids in terms of their physiological effect in small, under-powered studies with short observation periods. Meta-analyses based on these studies have consistently confirmed that crystalloids and colloids are equally effective plasma expanders [3]. The choice of an ideal plasma volume expander is often founded on personal belief as well as special ty and location of practice, and use of these compounds varies considerably throughout the world, with starches predominating in Europe, particularly Germany and the Netherlands as well as in Canada, while albumin is preferred in the USA and Australia. Gelatin is favored more in the UK. In the USA, by request of the FDA gelatin was removed from the market due to coagulatory side effects, whereas tetrastarch (HES 130/0.4) was recently introduced to the market [4].
In the meanwhile, however, clinical trials with suitable design and power were undertaken to study the effect of crystalloids or colloids in critically ill patients and the results provide new insights, especially on the safety of these compounds in these patients.
Albumin
Albumin is a natural plasma protein which contributes strongly towards plasma oncotic pressure. Albumin has an excellent long-term safety record and serious adverse events reported from its use are rare [5]. A highly controversial meta-analysis which focused on albumin alone found an increased mortality risk in critically ill patients [6] and led to a steep decline in use of albumin. However, this was neither confirmed by subsequent meta-analyses nor randomized controlled trials. The large interventional Saline versus Albumin Fluid Evaluation (SAFE) study was the first adequately designed study to investigate the outcome of albumin administration in critically ill patients [7]. Nearly 7,000 patients were randomized to receive either 4% iso-osmotic albumin or normal saline for resuscitation according to clinical status and response to treatment. In addition, patients received maintenance fluids, specific replacement fluids, and enteral or parenteral nutrition and blood products as necessary. Patients in the two groups received similar volumes of non-study fluid during the first 4 days except for the albumin group, which received 71.0 ml more of packed red cells. All outcomes in both groups were comparable, in particular the lengths of stay, number of organ failures, duration of mechanical ventilation, or 28-day all cause mortality [20.9% vs. 21.1%, the relative risk of death being 0.99; 95% confidence interval (CI), 0.91–1.09; p = 0.87].
The relative risk of death tended to be reduced in a subgroup of 603 patients with severe sepsis after resuscitation with albumin (30.7%) in comparison to saline (35.3%, p = 0.06 by the test for a common relative risk).
In a subgroup of patients with trauma, however, the relative risk of death during 28 days was higher in the albumin group (N = 1,186, 13.6% vs. 10.0%, 95% CI 0.99–1.86, p = 0.06). This was due to the greater number of patients with associated brain injury who died after random assignment to albumin as opposed to saline. A follow-up study of the enrolled patients with severe brain injury confirmed a significantly higher mortality at 24 months after treatment with albumin (N = 460, 33.2% vs. 20.4%, RR 1.88, 95% CI, 1.31–2.70; p <0.001) [8].
In summary, 4% iso-osmotic albumin is safe to use in the intensive care unit (ICU), except in patients with traumatic brain injury, and may have some potential
benefit in patients with severe sepsis. Further trials are needed to determine the relevance of this observation.
Hydroxyethyl Starch
Hydroxyethyl starch (HES) is the most widely used synthetic colloid and has been on the market for many decades. Previous meta-analyses concluded that HES does not improve clinical outcome compared to either other colloids or crystalloids [3,9]. Only few clinical studies in ICU patients have focused on patient-related outcome measures, and most of them were carried out only recently [1,2,10–13]. These studies compared fluid therapy with HES against crystalloid and confirmed that HES administration does not confer a clinical benefit. Moreover, they provide evidence that HES administration in ICU patients carries the risk of severe adverse effects and shows dose-related toxicity with increased long-term mortality. Meanwhile, the use of HES in critically ill patients is highly controversial [14,15].
The recent Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis study (VISEP) was undertaken to test the hypothesis that HES resuscitation would lead to a better outcome in patients with severe sepsis [2]. This prospective multicenter study randomized 537 patients to either 10% HES 200/0.5 or modified Ringer’s lactate to achieve a central venous pressure (CVP) >8 mmHg; in addition, patients received maintenance fluids, enteral or parenteral nutrition, and blood products. Twenty-eight-day mortality did not differ between the HES and the crystalloid group (26.7% vs. 24.1%, p = 0.48) but 90-day mortality tended to be higher in the HES group (41.0% vs. 33.9%, p = 0.09). Further analyses revealed that this was due to a substantial subgroup of patients (N = 100) who had received high doses of HES on at least 1 day (defined as >22 ml/kg body weight/day, 20 ml/kg/day being the dose limit recommended by the manufacturer). These patients also had received a cumulative dose of 136.0 ml/kg bodyweight and had an excessively high mortality rate of 57.9%, compared to the lower dose group with a median cumulative dose of 48.3 ml HES/kg and a mortality rate of 30.9%, p <0.001.
Wills et al. conducted a single center, randomized, double-blind comparison of Ringer’s lactate, 6% dextran 70, and 6% HES 200/0.5 for emergency resuscitation of children with Dengue shock syndrome stratified according to pulse pressure. The primary outcome measure was requirement for rescue colloid which was similar across treatment groups, the relative risk being 1.08 (95% CI 0.66–1.17; p = 0.38) for Ringer’s compared with either colloid solution [11].
Hypervolemic hemodilution is a widely accepted therapy in patients with acute ischemia of the brain. In order to test its efficacy, a recent double-blind, placebo-controlled study randomized 200 patients within 6 h of a first ischemic stroke localized in the middle cerebral artery territory to 10% HES 200/0.5 or Ringer’s lactate over a study period of 5 days. Primary outcome was clinical improvement within 7 days as measured by the Graded Neurologic Scale. An interim analysis showed that neurological recovery was similar between the groups at 7 days and 3 months and the study
was terminated early for futility [13]. The total dose of HES used was 2,500 ml within 5 days, which amounts to approximately 33 ml/kg cumulative dose in a 75 kg adult. Two subsequent small studies, which were undertaken with 10% and 6% HES 130/0.4 also failed to show a neurological outcome benefit over crystalloid [16,17].
Renal Impairment
There is now considerable evidence that HES can impair renal function in ICU patients, ranging from acute renal failure in prospective multicenter studies in septic patients [2,10] to chronic nephrotoxicity with secondary renal failure in liver transplant patients as long as 10 years after HES administration [18]. In patients with severe sepsis, administration of 6% HES 200/0.62 compared to 3% gelatin resulted in increased occurrence of renal impairment, defined as a twofold increase in serum creatinine from baseline or need for renal replacement therapy (N = 129; 42% vs. 23%, p = 0.028). The mean cumulative dose of HES was 31 ml/kg [10]. In the VISEP study, 10% HES 200/0.5 recipients had a higher risk of acute renal failure (34.9% vs. 22.8%, p = 0.002) and twofold days on renal replacement therapy (650 of 3,554 vs. 321 of 3,471 total days, or 18.3% vs. 9.2%). Renal impairment correlated with the cumulative dose of HES, but not of Ringer’s lactate. Importantly, patients who always received HES doses below the manufacturer’s daily dose limit still had a higher risk of renal failure than patients receiving crystalloid (p = 0.04) [2].
Safety of HES in critically ill patients has never yet been proven in adequately designed clinical studies. Studies called upon to rule out negative effects of HES solutions on renal function are flawed by inadequate comparators, e.g., other synthetic colloids like different HES solutions or gelatin, too-short observation periods, and inadequate endpoints for renal dysfunction [4, 19]. With observation periods of 5 days or less and creatinine serum levels as marker of renal dysfunction, neither the Schortgen [10] nor the VISEP study [2] would have revealed the higher incidence of renal failure after HES administration.
Similarly, findings from a recent European multicenter study which claimed that HES was not associated with increased renal replacement therapy are inconclusive because the study was purely observational and not designed to test the safety of HES. Patients received other colloid fluids and HES use was reported in a very low mean cumulative dose of less than 15 ml/kg [20]. Another recent comparison in cardiac surgical patients with 60-day follow-up concluded that HES 130/0.4 was as safe as 5% albumin; however, the cumulative dose during the 48-h study period was only approximately 33 ml/kg, which is less than one recommended daily dose of 50 ml/kg [21].
In 2007, use of tetrastarch (HES 130/0.4) in the USA was approved by the FDA for hypovolemia during or after surgery on the basis of noninferiority studies. The underlying clinical studies, which can be publicly assessed [4], show that comparator fluids were mainly other starches or gelatin. Estimation of safety was based on pooled results from studies in low risk patients excluding previous cardiac surgery; anemia; a history of heart, kidney, or liver disease; diabetes or severe infectious diseases; history of coagulation disorders; known allergy to starch; BW >100 kg; pregnancy; and lactation. Mean observation period was 2 days and mean cumulative dose was 42 ml/kg, which is less than one daily allowed maximum dose of 50 ml/kg for this solution. There was no data on the safety of HES 130/0.4 in severe sepsis patients or ICU patients with pre-existing renal impairment or risk for renal dysfunction. Based on this evidence, HES 130/0.4 can only be safely recommended in small amounts and in patients with low risk [4]. Adverse effects on renal function have been noted in various clinical conditions and for all HES solutions [22,23]. Recently, persisting renal failure with osmotic nephrosis and interstitial foam cells was observed in a previously healthy patient with severe sepsis who had received fluid resuscitation with the most modern HES 130/0.4 in a cumulative dose of 81 ml/kg within 5 days [23].
The mechanism of renal failure is unclear. HES and dextran are taken up by the proximal tubular cells leading to swelling and subsequent lesions called osmotic nephrosis. The pathophysiology can be described as accumulation of proximal tubular lysosomes due to administration of exogenous solutes [24]. In the critically ill patient with hypovolemia or shock, such lesions may contribute to acute or chronic renal failure. Schortgen et al. have suggested that the use of hyperoncotic colloid solutions, i.e., starches, dextrans, and 20–25% albumin may be responsible for renal impairment [25].
Coagulopathy and Thrombocytopenia
HES interferes with clotting factors, thrombocytes, and prolongs bleeding time [26]. It may lead to potentially fatal bleeding in susceptible patients. A meta-analysis investigating perioperative blood loss in 653 cardiac surgical patients from 16 trials with albumin or HES exposure found that blood loss amounted to 789 ±487 mL in the HES group compared to 693 ±350 mL in the albumin group, the pooled standardized mean difference reaching statistical significance. Interestingly, increased bleeding was equally associated with HES solutions 200 or 450 kDa; and mean cumulative doses were 15.0 ml/kg and 8.9 ml/kg, respectively. Albumin moreover resulted in significantly less bleeding than HES in comparisons involving both volume expansion and addition of colloid to the priming fluid [27]. As a result, the FDA added a warning label on the package insert for hetastarch (HES 450 kDa), the only HES solution then on the US market, stating that this solution “is not recommended for use as a cardiac bypass pump prime, while the patient is on cardiopulmonary bypass, or in the immediate period after the pump has been discontinued because of the risk of increasing coagulation abnormalities and bleeding in patients whose coagulation status is already impaired.” [28]. In France, HES 200/0.62 was withdrawn from the market after a pharmacovigilance study documented three cases of fatal cerebral hemorrhage among nine patients with subarachnoid hemorrhage and acquired von Willebrand’s disease after HES exposure [29]. In patients with acute ischemic stroke or brain injury with cumulative HES doses of approximately 70, 87, and 253 ml/kg
[16,17,30] raised safety concerns about increased incidence of intracranial bleeding [31,32]. Another group of patients at increased risk are patients with severe sepsis, where administration of 10% HES 200/0.5 compared to Ringer’s reduced the platelet count (p <0.001) and was associated with transfusion of more units of packed red cells (p <0.001) [2].
Tissue Uptake and Storage
In critically ill patients with disturbed macro-und microcirculation, vascular leakage, and renal impairment, lysosomal uptake in the lysosomes of reticuloendothelial cells with subsequent tissue storage becomes a major route of elimination for HES molecules from plasma. HES thus may accumulate dose dependently in a variety of organs [33], particularly after repeated administration. Pruritus after HES is due to deposition in the skin, most probably in cutaneous nerve fibers [34] and can lead to protracted and long-lasting itching depending on the cumulative dose [35]. Pruritus is associated with all HES solutions, and was observed after hemodilution therapy with HES 130/0.4 to a higher degree than HES 200/0.5 [4]. Chronic administration can result in massive HES storage in macrophages, bone marrow, and liver cells with the aspect of a storage disease, manifesting as “foamy macrophage syndrome” or “acquired lysosomal storage disease” with liver failure and ascites [36, 37]. These patients had received cumulative HES doses in the range of 250 to 400 ml/kg or more for plasmapheresis or fluid therapy on the ICU.
Issue of Cumulative Dosage
It is becoming increasingly clear that HES-related toxicity is dose dependent and relates more closely to the overall cumulative rather than the maximum daily dose administered. In the VISEP study, need for renal replacement therapy increased almost linearly with cumulative doses of HES [2]. Awareness of cumulative dosage is still low. Manufacturers mostly recommend daily dose limits but do not mention cumulative dose thresholds. Cumulative doses are not routinely reported in HES trials, and large daily doses exceeding recommendations are not unusual in clinical studies or in daily clinical practice [30,38]. Use of HES should urgently be restricted to the cumulative doses which were found to be safe in clinical studies with adequate observation periods.
Dextran and Gelatin
Dextran and gelatin are synthetic colloids which share important characteristics with starches, namely their dose-related renal and coagulatory side effects [5,26] and their inability to improve clinical outcomes compared to albumin or crystalloids [1,3,11,12,39].
Dextran is a polydispersed mixture of glucose polymers. It is associated with severe anaphylactoid reactions and has been increasingly replaced by gelatin or HES. Wills et al. compared 6% dextran 70 with Ringer’s lactate for emergency resuscitation of children with Dengue shock syndrome and found that dextran use conferred no clinical benefit [11].
Gelatin is a bovine collagen derivative which was withdrawn from the US market as plasma volume expander in 1978 due to increased blood viscosity, reduced blood clotting, and prolonged bleeding time (http://www.fda.gov/ohrms/dockets/ 98fr/ 100898b.txt). Similarly, A well-conducted comparison between normal saline and gelatin for resuscitation in 60 children with septic shock showed that both performed equally in terms of hemodynamic stabilization. Both fluids were titrated to blood pressure, capillary filling time, or central venous pressure [39]. Gelatin impairs hemostasis during cardiac surgery as compared to albumin [40] and perioperative renal function in aortic aneurysm surgery compared to HES [41]. Anaphylactoid reactions are 4–6 times more common after gelatin than after HES or dextran (pooled incidence rate ratio in comparison to albumin 12.4; 95% CI 6.4–24.0) [5]. Gelatin has been found to result in a lower incidence of acute renal failure in severe sepsis in comparison to HES 200/0.62 [10], but comparisons to albumin or crystalloids in adult septic patients are lacking.
Crystalloids
Crystalloids contain water and electrolytes and are fluids without oncotic pressure, including normal or isotonic saline (0.9% NaCl), acetated or lactated Ringer’s, or Hartmann’s solution.
Hypertonic saline is still considered experimental in humans, except for the treatment of raised intracranial pressure and cerebral edema following traumatic brain injury [42]. Small volume resuscitation fluids are a combination of hypertonic crystalloid with a colloid, e.g., 7.5% sodium chloride and 6% dextran 70. A recent meta-analysis could not arrive at a conclusion about the efficacy of hypertonic crystalloids for lack of adequate data in patients with trauma, burns, or those undergoing surgery [43].
Saline-based fluids can lead to the development of hyperchloremic acidosis; this may not necessarily harm the patient. In surgical patients, volume therapy with normal saline required administration of bicarbonate, more total fluid, and more blood products than with Ringer’s. This, however, had no direct effect on ICU or hospital stay and adverse events [44].
Crystalloids are devoid of allergic reactions or the side effects discussed above, are completely eliminated, and cheap to use. They have, however, been shunned for fear of pulmonary and tissue edema. Recent studies, however, have shown that the volume requirement for successful resuscitation is not as high as believed and considerable fluid loads did not lead to pulmonary edema. In septic patients, median respiratory SOFA score was 1.76 (interquartile range 1.00 to 2.71) in the Ringer’s group and 1.80 (IQR 0.86–2.67) in the HES group (p = 0.51) [2]. Similarly, in a study comparing resuscitation fluids in 67 mechanically ventilated surgical patients with acute lung injury, determination of the 67Ga-transferrin pulmonary leak index and extravascular lung water showed no difference and oxygenation ratios improved in all groups. Pulmonary permeability and edema were not affected by different colloids or crystalloid administered for volume loading, despite the fact that significantly more saline than HES, albumin, or gelatin was used [12].
Differences in Hemodynamic Effects Between Crystalloids and Colloids
The current understanding and one of the arguments used in favor of colloids is that they expand the intravascular volume and increase myocardial preload faster than crystalloids [45]. However, larger studies and longer observation periods reveal that this effect is marginal and does not lead to improved clinical outcome in the ICU [2,7,11]. When septic patients with below target values of CVP, central venous oxygen saturation (ScvO2), and mean arterial blood pressure (MAP) were resuscitated with HES or Ringer’s, only CVP returned to target more quickly after HES (p = 0.003). ScvO2 and MAP normalized equally fast with modified Ringer’s lactate, and clinical outcomes were comparable [2]. Children with Dengue shock syndrome who received colloids achieved initial cardiovascular stability more rapidly and showed a faster reduction in median hematocrit values during the first 2 h (25, 22, and 9% reduction for dextran, gelatin, and Ringer’s, respectively; p <0.001). Subsequently, however, their hematocrit increased more than with Ringer’s (5% increase for dextran or gelatin, 0% for Ringer’s; p <0.001). The authors explained this as a combination of fluid effects and vascular leak, such that colloids exerted a rapid effect followed by a rebound increase in vascular leak a few hours later. Overall time to final stabilization was not different between groups [11].
It is commonly believed that it requires 3–5 times more crystalloid than colloid volumes to raise the circulating intravascular fluid to a similar degree [46]. This concept was derived from small studies in surgical and septic patients with short observation periods. More recent studies reveal that considerably smaller volume ratios of colloid to crystalloid were needed in direct comparison for comparable clinical outcomes, ranging from 1 to 1.0 for HES or dextran [11], 1 to 1.2 for colloids [1], 1 to 1.4 for albumin [7], 1 to 1.4 for HES [2], 1 to 1.6 for gelatin [39], and 1 to 1.7 for colloids [12]. In summary, the evidence from these more recent studies strongly suggests that resuscitation with crystalloids in critically ill patients to the same hemodynamic goals does not require several-fold volumes and longer time to achieve than with colloids. The most likely reason may be that in critically ill patients with increased vascular leakage, colloids do not remain much longer in the vasculature than crystalloids.
Conclusions
Recent evidence confirms that the use of gelatin, dextran, or HES as plasma volume expanders in critically ill patients does not add a survival benefit in comparison to crystalloids. All synthetic colloids are associated with dose-related harmful effects, in particular coagulopathy and renal impairment. Moreover, HES is taken up and stored in various organs; this may be detrimental in ICU patients, in particular patients with sepsis. HES also raises safety concerns in patients with brain injury. Unfortunately, adverse effects were also observed with the most modern HES solution (HES 130/0.4, Voluven®).
While a potential benefit for albumin was shown in patients with severe sepsis which has to be confirmed in further clinical trials, albumin too is very likely to be harmful in patients with traumatic brain injury. Crystalloids are as effective as colloids but safer for resuscitation in critically ill patients. Longer observation periods show that the fluid requirement to achieve similar hemodynamic goals is not considerably higher for crystalloids than colloids and frequency of pulmonary edema is not increased.
Because synthetic colloids do not improve outcomes, but can cause considerable harm, the question arises whether they still have a place as plasma expanders in these high-risk patients. Notwithstanding, use of HES should urgently be restricted to the cumulative doses which were found to be safe in clinical studies with adequate observation periods.
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