The challenge of maintaining control of patient physiology in the ICU

Introduction
Apart from uncomplicated postoperative care after major surgery, ICU patients frequently suffer from complex manifestations of organ dysfunctions (for example, heart, lung, brain intestines, kidney and liver) frequently complicated by causal or concomitant infections. Due to complex systemic effects of different diseases, sequential multiple organ dysfunction and failure (MOD/MOF) may develop, which has advanced to the predominant reason for increased mortality.

Based on the realisation that typical ICU diseases reflect the consequences of severe systemic changes which expand the severity of the initial disease, rapid restoration and maintenance of patient physiology may be of crucial importance in order to limit potentially devastating effects and consequences of impaired tissue perfusion and organ dysfunction.

In addition to the knowledge of basic treatment concepts of intensive care medicine including for example, fluid management, nutrition, respiratory support, and anti-infectious therapy, treating physicians must be knowledgeable in the disease-induced cascades and associated MOD/MOF. Insufficient cognition will promote morbidity and mortality caused by these alterations inherent to MOD/MOF.
 
Pathophysiology
Sepsis, shock and severe trauma are followed/accompanied by a systemic reaction characterised by immunologic, neuroendocrine, microcirculatory and coagulatory alterations. These functionally interwoven cascades are activated sequentially and in parallel. The typical findings are:

• Acute phase reaction with the aim of activating the immune system, initiating a host defence and promoting reparative processes.
• Inflammation (that is, systemic inflammatory response syndrome [SIRS]) and increased endothelial permeability.
• Anti-inflammation potentially progressing to immunoparalysis (that is, compensatory anti-inflammatory response [CARS]) subsequent to the initial SIRS.
• Neuroendocrine response and metabolic alterations.

Trigger as well as modulation of these reactions result from different initiators (that is, complement, bacterial lipopolysaccharides, disturbed microcirculation as well as alterations induced by ischaemia/reperfusion). Moreover, endogenous (for example, hypoxia, repetitive cardiovascular instability/ hypovolaemia, disturbed coagulation, metabolic acidosis, tissue necrosis, and infections) or exogenous causes (for example, extensive surgical interventions with additional tissue damage, extensive blood loss hypothermia, mass transfusions, inadequate or delayed surgery as well as inadequate or delayed intensive care treatment) amplify inflammatory, neuroendocrine, and metabolic responses.¹ The resulting extensive SIRS, which can induce multiple organ dysfunction and progress to multiple organ failure, substantially contributes to an increased morbidity and mortality. In this context, both, levels of cytokines as well as duration of elevated cytokine concentrations correlate with the severity of injury and are associated with an increased susceptibility to subsequent infections and mortality. In addition, the subsequent impaired cellular immunocompetence is clearly associated with an increased risk of developing infectious complications, which in turn are associated with an increased mortality.² Consequently, this explains why additional insults known to amplify destructive cascades must be avoided. In addition, perfect timing of potentially damaging interventions is indispensable.

Apart from the more obvious findings which can be measured and observed at bed side several additional factors as that is, genetic predisposition and gender-dependency have been identified to influence morbidity and mortality.

Aimed at reducing the adverse events in the ICU thereby decreasing release of trigger factors novel strategic concepts (for example, early goal directed therapy) were developed and implemented in clinical routine.
 
Intensive care
Intensive care consists of supporting the endogenous compensation mechanisms and reparative processes by optimising substrate delivery (for example, oxygenation, perfusion, nutrition), temporary artificial support of organ functions in case of reversible organ failure, and prevention of secondary damage. The overall aim is to create a condition allowing subsequent healing and recovery.

It is of utmost importance to practice a holistic approach, that is, to understand the patient in its complete complexity and to guarantee an adequate and timely flow of information between the different involved disciplines. Especially for the complex ICU-patient an interdisciplinary approach is indispensable to identify problems fast, to react adequately and to develop a strategy based on the individual development and regression. Moreover, targets and interventions have to adapt to the individual needs as so called “normal” values and “recipe-book” approaches frequently do not apply for the critically ill.

Special considerations
Circulation
Besides of primary cardiac failure (for example, impairment of pump and/or valve function, or severe lung embolism) severe hypovolaemia up to hypovolaemic shock following severe sepsis or bleeding is the most deleterious alteration, which determine subsequent development and incidence of potentially devastating consequences. The most prominent pathophysiologic consequence is microcirculatory failure resulting from hypovolaemia and subsequent sympathico-adrenergic pre-capillary vasoconstriction. These changes may be accompanied by NO-induced vasodilation, which in turn causes shunts and impairs nutritive capillary perfusion explaining heterogeneous capillary perfusion impairment. As a consequence, compromised organ perfusion with evolving tissue ischaemia and lactate production with sustained increase in endothelial permeability will aggravate the underlying condition due to progressive oedema formation. In case of persisting ischaemia degradation of energetically rich phosphates in conjunction with free oxygen radical induced mitochondrial damage will result in irreversible functional and finally structural cell injury. The degree of this damage strongly depends on the extent and duration of the underlying tissue ischaemia. Resulting from restored perfusion reperfusion injury is feared for its generation of highly toxic free oxygen radicals. These, in turn, are known to damage cell membranes by peroxidation of cell membrane lipids accounting for resulting vasoplegia and swelling.

Fluid resuscitation consecutively allowing for savings of exogen vasoactive drugs therefore is a mainstay of critical care and one of the most frequent interventions in ICU patients. The overall accepted aim is to swiftly restore a sufficient circulation (by far not simply restoring a “normal” arterial blood pressure), maintain haemodynamic stability by improving organ perfusion and microcirculation. The primary goal is the quantitative restoration of intravascular volume guided by haemodynamic parameters, restoration of peripheral perfusion, restitution of sufficient diuresis, and reduction or normalisation of arterial lactate, pH, and base excess values. In this context persistent acidosis (pH <7.2) as well as negative base excess values were shown to significantly predict outcome. Perhaps more important than the absolute values is the fact how long it takes to normalise lactacidosis and negative base excess during adequate treatment consisting of volume management, and haemodynamic support. Persisting negative base excess and lactacidosis exceeding 24 hours is clearly associated with significantly increased morbidity and mortality.³ Lactate-guided volume management is associated with significant reduction in mortality. Strategies using crystalloids alone promote tissue oedema due to extensive extravasation and therefore compromise tissue oxygenation and organ function. This may explain why alternative resuscitation fluids are needed and still widely in use. However, since publication of different studies a not always very rational but nevertheless very intense controversial discussion has raised again whether use of colloids and especially hydroxyethylstarch (HES) may increase mortality and/or renal failure. Meanwhile, several large-scale studies about fluid replacement in different ICU populations including those with sepsis and hypovolaemic shock were published in high-ranking journals.^4,5 In summary, it can be concluded that there is still a good place for colloids in fluid resuscitation provided that only severe hypovolaemia is treated, that modern isooncotic starches are used and that sufficient amounts of crystalloids for maintenance fluid balance are given. This also may hold true for patients with severe sepsis induced hypovolaemia.

Estimation of fluid requirements still is a great challenge. On one hand, counter regulatory mechanisms as well as vasoplegia in septic patients may disguise typical clinical features seen in hypovolaemic patients. Classical parameters such as blood pressure, central venous pressure have been proven to be unreliable to estimate fluid requirements as they are influenced by many factors (that is, positive pressure ventilation, impairment of pump function, veno-tone, sympaticotone) and increased lactate levels are very specific but not very sensitive as they demonstrate tissue ischemia which already is established. Recent studies in patients with septic shock demonstrate that targeting higher blood pressure, and haemoglobin levels have no outcome advantage compared to standard therapy, provided hemodynamic stabilisation is addressed timely.^6,7 Moreover, in the most recent large-scale study⁸ it could be shown, that in patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict early goal directed (EGDT) protocol as proposed by Rivers in 2001 did not lead to an improvement in outcome.^8,9

During the acute phase the patient’s microcirculation is very vulnerable. Fluid overload compromises the glycocalyx and may thus potentiate oedema.¹⁰ Once a SIRS is induced, capillary leak leads to a local loss of control of inflammatory mediators and further increases oedema.

In summary, volume expansion will improve cardiac output to a certain point via the Starling mechanism. Beyond that point it will, however, worsen cardiac function and promote oedema formation. Therefore, monitoring of stroke volume and cardiac output before and after fluid challenge is a more reliable alternative than assessing heart frequency and blood pressure alone. Moreover fluid challenges with larger fluid boluses may compromise glycocalyx and thus promote capillary leakage and oedema formation especially in non-hypovolaemic states.

Fluid resuscitation and the bowel system
In recent years, several studies have shown that an increased administration of sodium and water may have numerous detrimental effects on the gastrointestinal system: the oedema in the splanchnic area leads to intestinal oedema, impairment of healing of surgical anastomoses, and an increase in intra-abdominal pressure that in turn can lead to a decrease of tissue oxygenation. Apart from intestinal permeability dysfunction, which is suspected to account for increased bacterial translocation, a protracted dysmotility of the bowel can be observed, causing intolerance to enteral nutrition. The resulting gastrointestinal dysfunction increases the risk of ventilation-associated pneumonia and therefore increases morbidity and mortality, as well as length of stay in the ICU and time to discharge.¹¹ Given these pathophysiological effects of crystalloid fluid infusion, alternative volume replacement strategies are warranted using colloid fluids, and considering early administration of vasopressors in order to restore vascular tone.    

Respiration
Respiratory failure is commonly encountered in ICU patients. In severe respiratory failure resulting from a pulmonary disturbance (pneumonia, acute respiratory distress syndrome (ARDS), lung contusion, aspiration), endotracheal intubation, and mechanical ventilation often cannot be avoided. In general, however, modern ventilation strategies aim at keeping ventilator support as short and least invasive as possible. Restriction of controlled ventilation lies in the fact that it causes a myriad of undesired effects and carries risks (circulatory depression, ventilator-associated pneumonia, alveolar volutrauma and barotraumas, etc.) that can lead to increased morbidity and mortality, as well as a prolonged LOS in the ICU and hospital.

Mechanical ventilation
Since its introduction in the early 50s of the last century, mechanical ventilation has become an indispensible tool to save life especially in, but by no means limited to, respiratory compromised patients.

The recognition that mechanical ventilation, although life saving, can contribute to patient morbidity and mortality has been the most important advance in the management of ventilated patients especially those patients with acute respiratory distress syndrome (ARDS). If mechanical ventilation is indispensable, ventilator induced lung injury must be avoided. Central elements comprise limitation of tidal volume (that is, ≤6ml/kg body weight, depending on the severity of lung injury, in order to avoid volutrauma, as well as limiting peak inspiratory pressure  ≤30mbar to avoid barotrauma (so-called “Lung Protective Ventilatory Strategy”). Over the years, many dogmas of mechanical ventilation have dramatically changed. The application of external positive end-expiratory pressure (PEEP) in patients with exacerbated chronic obstructive pulmonary disease (COPD) or asthma, having been abandoned over decades, now has become a standard procedure provided external PEEP is set below the level of the so-called intrinsic PEEP. Similarly, the acceptance of elevated arterial carbon dioxide partial pressure (PaCO₂) in patients with ARDS (known as permissive hypercapnia) has been widely accepted to prevent potential harmful ventilatory settings otherwise necessary to keep the PaCO₂ within “normal” ranges. Furthermore, the trend to allow for supported spontaneous breathing instead of fully controlled mechanical ventilation in the early and, thus, less stable phase of ARDS is another example of a dogma that becomes increasingly changed. Switching to assisted spontaneous breathing modes as early as possible has shown to improve gas exchange by redistribution of ventilation in to dependent lung areas, improves systemic blood flow, and tissue oxygenation compared to controlled mechanical ventilation.¹² Another advantage lies in the lower requirement for sedation, which again may lead to a shorter LOS in the ICU. Last but not least, there is increasing evidence that non-invasive ventilatory support via a face mask or similar devices can successfully augment ventilation and prevent tracheal intubation in patients with acute cardiogenic pulmonary oedema, exacerbated COPD, or possibly also in patients suffering from ARDS. Techniques such as extracorporeal CO₂ removal and extracorporeal membrane oxygenation (ECMO) are currently utilised in many tertiary care centres in order to prevent ventilator induced lung injury while aiming for a sufficient gas exchange, and to allow for spontaneous breathing and even prevent intubation respectively.

Bowel system, microbiome, and nutrition
For hundreds of thousands of years a symbiotic relationship between colonising flora in the host (today called the microbiome) has emerged to benefit both parties. The human intestinal microbiome is composed of >1×10¹⁴ bacteria from 500–1000 different species. It represents over nine million different genes (human genome features about 20,000 genes). Therefore humans somehow are “bacterial” as more than 90% of the cells humans carry around are bacterial.¹³ Recent recognitions advocate the adoption of the microbiome as an additional secretory organ performing myriads of indispensable tasks for its host. It could be shown that bacteria of the microbiome interact with local tissues that they have colonised and are involved in the development of the mucus layer why they are an indispensable component of the local tissue physiology. Bacteria stimulate and modulate the muscosal immunity¹⁴ and play a crucial role in the development of the systemic immune system especially in early childhood.¹⁵ They participate in metabolism/fermentation of non-digestible food particles, the production of essential vitamins (that is, K and B), provide energy (by producing short chain fatty acids (SCFA) and other substrates), maintain the balance between different germs preventing bacterial overgrowth of pathogens, and profit from the host in symbiotic manner (by nutrients, substrate supply etc.). The impact of the intestinal microbiome, however, does not stop at the gut. Metabolites, that is, SCFAs, are partly taken up by intestinal epithelial cells (IECs) while another portion enters the systemic circulation. SCFAs and butyrate (esters and salts of butyric acid, a SCFA) have an anti-inflammatory effect on leukocytes. Components of the intestinal microbiome are translocated into the systemic circulation and continuously prime neutrophils leading to enhanced capability of these cells to kill pathogens. Furthermore, there exists a bi-directional communication between gut and brain (gut-brain hypothesis). Mucosal and systemic immune system influence gut and brain and brain stem can send signals in both directions via spinal chord and autonomous nerve system. In the gut and the enteric nervous system neurotransmitters and neuropeptides influence physiology, development, and function of the gut and the central nervous system. There are several diseases (that is, allergies, inflammatory bowel diseases, chronic abdominal pain, eating disorders including obesity, alterations in stress reactions and behaviour, depressions, and autism) closely linked to dysbiosis of the intestinal microbiome. Therefore, it becomes obvious that protection of the human microbiome is of crucial importance for the hosts’ wellbeing and its protection already starts with birth, that is, natural delivery instead of C-section,¹⁶ breast feeding, and includes quality of food ingested, that is, pre/probiotics, meat from animals not treated with antibiotics etc.¹⁷

Modern advances in medicine allowing for treatment of critically ill and compromised patients including use of potent antimicrobials forced the intestinal flora to adapt and develop strategies to survive against threats originating from a hostile environment and attempts of its extermination. Research work has shown that for this purpose microbes are able to communicate, to organise in functional communities and to regulate their virulence in order to protect their self-interests. It could be demonstrated that this germs mainly generate adverse effects against the host by interacting with his epithelial cells that is, in the intestines. By doing so the bacteria can induce paracellular permeability defects promoting translocation of toxins with systemic downstream effects. Moreover some germs are able to corrupt and exploit host cellular function in order to satisfy their needs leading to harm to the host more as a collateral damage.¹⁸ In the future treatment concepts to prevent devastating effects of “gut derived sepsis” should therefore become directed towards optimisation of microbial frame conditions in order to minimise their need to up-regulate virulence and thus jeopardise the host. In such a concept new targets have to be defined conforming conceptually to a settled negotiation within the dynamic interplay between host and pathogen: once, host injury subsides and pathogens sense a normal environment and customary food supply, the self-interests of each party are satisfied and homeostasis can return.

The bowel system acts a classic shock organ and is almost inaccessible to clinical and diagnostic tests. This may lead to compromising events that are not being noted and treated in a timely manner. Complications such as SIRS, severe infections, or sepsis are characterised by a splanchnic hypoperfusion and increased oxygen consumption caused by stress hormones, an increased hepatic gluconeogenesis, and cytokine-induced hypermetabolism leading to a mismatch between actual oxygen consumption and available oxygen. Among others the gut mucosa, lined with enterocytes, which play an important role in the pathogenesis of MOF suffers from this dysbalance resulting in an increased permeability for bacteria and toxins most probably promoting various adverse systemic effects. In order to limit damage to the mucous membrane, to improve milieu for the microbiome colonising the intestines and to restore splanchnic perfusion volume therapy and shock treatment, as well as endoluminal administration of substrates is essential. Today it is well recognised that topic substrate delivery into the intestines is important for maintenance/restoration of gut integrity. Therefore, oral/enteral nutrition most probably is superior compared to parenteral nutrition. However, recent studies also clearly demonstrate that provision of sufficient amounts of calories and proteins is equally important to avoid devastating effects from calorie-protein malnutrition. Therefore, supplemental parenteral nutrition is warranted if oral/enteral nutrition cannot provide sufficient calories and proteins within the first three to five days after ICU admission.¹⁹

Kidneys
Renal failure in ICU patients has a significant impact on mid- and long-term survival. The pathophysiology of acute renal insufficiency/failure in the ICU frequently is driven by hypovolaemia. Ischaemia, focal hypoxia, and dysfunction of the coagulation system lead to functional and structural damage of the kidneys presenting itself clinically as oligo/anuria. Moreover, nephrotoxic drugs may be directly responsible for disruption of renal autoregulation or may aggravate pre-existing renal insufficiency. Therefore, a central element of preventing acute renal failure is urgent and also decisive correction of hypovolaemia, avoiding hypotensive states fluid overload, and avoid nephrotoxicity. There are no other possibilities of protecting the kidney; neither application of dopamine nor administration of diuretic drugs has any scientific basis. On the contrary, it is most likely that such interventions will lead to a deterioration of renal function (for example, because of worsening of renal energy homeostasis). In the event of acute oligo/anuric renal failure, continuous renal replacement therapy should be employed. It has been shown that, continuous renal replacement therapies are superior to intermittent dialysis at least with respect to renal recovery and long-term survival.^20,21

Infections
Infections in critically ill patients in the ICU are more common than in most other parts of the hospital, and are often the most complicated to manage. Underlying disease and the reasons for admission make the diagnosis, management and prevention of infection challenging. Developments in technology, the treatment of previously untreatable malignancies, complex surgery procedures, and an increasing age profile result in more patients vulnerable to infection and a greater number of patients needing critical care support. Community-acquired infections and nosocomial infections both contribute to the high level of disease acquisition common among critically ill patients. The accurate diagnosis of infections and the provision of appropriate therapies, including timely initiated antimicrobial therapy effective against the agents of infection (that is, in sepsis), have been shown to be important determinants of patient outcome.

Critical care practitioners are in a unique position as they are often the initial providers of care to seriously ill patients with infections. Additionally, they have a responsibility to ensure that nosocomial infections are prevented and that antimicrobial resistance is minimised by prudently employing antibiotic agents. Moreover, search and adequate treatment for infectious foci is indispensable for survival and recovery of the ICU patient.

Conclusion
To conclude the cornerstones to meet the challenge of maintaining control of patient physiology in the ICU include various strategies to restore physiology in a timely manner addressing the various pathways potentially leading to devastating conditions, which may jeopardise the critically ill patient. A major challenge is to find the balance between life support needed and side effects of the treatment applied.

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