Pediatric Nephrology

Pediatr Nephrol (1992) 6:88-95 9 IPNA 1992

Practical pediatric nephrology Critical care in uraemic children Jekabs U. Leititis and Matthias Brandis Department of Paediatrics, University of Freiburg, Federal Republic of Germany Received August 13, 1991 and accepted August 16, 1991

Abstract. The special problems posed by renal disease have to be considered when a uraemic child requires intensive care. This report gives an overview on the problems of dialysis treatment, circulatory support, infectious complications, coagulation disorders and increased intracranial pressure. Key words: Chronic kidney failure - Respiratory therapy - Dialysis - Blood coagulation disorders - Intracranial pressure - Catecholamines - Bacterial infections

Introduction In addition to all the problems of intensive care treatment of uraemic children has to take into account the peculiarities resulting from pre-existing renal disease. Additional techniques have to be instituted and medical treatment has to be adjusted to the degree of renal dysfunction. Therapeutic approaches which depend upon the excretory capacity of the kidneys have to be modified.

Dialysis on the intensive care unit If the patient has been on maintenance dialysis before entering the intensive care unit (ICU), this treatment has not only to be continued but may even need to be intensified due to the resulting hypercatabolism. Critically ill patients with pre-terminal renal insufficiency can develop terminal renal failure. Dialysis becomes necessary if fluid balance cannot be preserved by other means, and if normocaloric nutrition or even hyperalimentation is being prevented by the constraints of volume restriction.

Offprint requests to: J. U. Leititis, Kinderklinik der Albert-LudwigsUniversit~tt, Mathildenstrasse 1, W-7800 Freiburg, Federal Republic of Germany

The method of dialysis applied depends on the facilities of the individual unit. The least technical facilities are required with continuous or intermittent peritoneal dialysis (PD). Limitations or contraindications for PD are: respiratory insufficiency aggravated during peritoneal filling, paralytic ileus or post-surgical abdominal drainage. Owing to its technical simplicity continuous arteriovenous haemofiltration (CAVH) is now a widely accepted method in ICUs [1]. The predominant indication for this method is an otherwise therapeutically resistant fluid overload. With CAVH, parenteral nutrition can be provided even in oliguric patients. By using miniaturized filters this technique can be applied even to premature infants [2-4]. However, CAVH still has some limitations; as it is performed without any dialysis monitor, volume replacements for fluid balance have to be controlled manually; despite optimal fluid removal, uraemic toxins may not be removed appropriately, particularly if blood flow is low. This flow can be raised by insertion of a blood pump, allowing modification of the technique to venovenous haemofiltration (CVVH), now using a single cannulated vessel [5]. With increasing transmembranous pressure by application of a negative pressure on the ultrafiltrate side, the ultraflltration rate and solute exchange can be enhanced [6]. Additionally, the solute exchange can be enhanced by countercurrent infusion of a dialysate into the ultrafiltrate compartment, thus performing a haemodiafiltration [7]. The above modifications significantlyincrease the expense of the required monitoring. A haemofiltration monitor is advisable for patient safety reasons. This machine-monitored haemofiltration requires no special installations on the ICU, unlike haemodialysis (HD). For all the above-mentioned methods of extracorporeal blood purification the biocompatibility of dialyser membranes and, in the case of HD, the use of acetate or bicarbonate dialysates, have to be considered. While these technical details play a minor role in dialysis of otherwise healthy children, in intensive care patients they can be of great significance. Symptomatic hypotension is a frequent complication of HD, especially if performed with a dialysate buffered with

89 acetate. Bicarbonate dialysis should therefore be used in critically ill patients with cardiovascular instability. Additionally, the rate of tolerable ultrafiltration is higher in bicarbonate than in acetate dialysis [8]. Acetate causes vasodilatation resulting in hypotension if cardiac output cannot be increased, e.g. in compromised left ventricular function [9]. Bicarbonate dialysis shows a greater improvement of left ventricular function [10]. This difference is even more pronounced in pre-existing left ventricular insufficiency [11]. Plasma volume preservation is significantly lower during acetate dialysis, which might be a combined effect of peripheral vasodilatation, cardiodepression and impaired baroreceptor function [12, 13]. Haemofiltration and CAVH are tolerated better in cardiovascular instability. More fluid can be removed without hypotensive reactions than by HD [14, 15]. Plasma osmolality remains nearly unchanged during haemofiltration [ 16]. Despite greater removal of fluid, the reduction of extracellular space is less pronounced than with dialysis, in which a significant shift from interstitial to intracellular volume occurs due to the rapid drop in extracellular osmolality. Additionally, peripheral vascular resistance increases during haemofiltration, but not during HD [17]. This effect is caused by a rise in circulating catecholamines, only present during haemofiltration [18]. The least circulatory problems can be expected from PD. If respiratory insufficiency is the result of volume overload, fluid reduction by dialysis can correct diffusion abnormalities. On the other hand, dialysis itself can induce hypoxaemia. This is mainly due to the use of acetate buffer and not due to the marked neutropenia occurring during the first minutes of dialysis, which is caused by cell clumping, sequestration and aggregation in the pulmonary vessels [19]. The latter phenomenon is related to the biocompatibility of dialyser membranes, polyacrylonitrile leading to a less-pronounced neutropenia than cuprophane or cellulose [20]. The degree of leucopenia is not directly related to complement activation as both phenomena seem to be unrelated processes triggered by the dialyser membranes. This has been shown by comparing different biocompatible membranes where neutropenia occurred without activation of the alternative pathway and vice versa [21, 22]. Whether the pulmonary cell sequestration reaches relevance in cardiopulmonary compromised intensive care patients has not been fully elucidated. There is, however, some evidence that neutrophils harvested during dialysis when neutropenia is most pronounced do show some functional impairment [23, 24]. To reduce such changes to a minimum, biocompatible membranes should therefore be carefully selected for intensive care patients. Dialysis-induced hypoxaemia is a feature of acetate but not of bicarbonate dialysis, also occurring with biocompatible membranes when leucopenia is minor [25]. The cause is alveolar hypoventilation [26, 27], not related to the correction of acidosis [28] but to a decrease in pulmonary carbon dioxide (CO2) excretion. This decrease in CO2 delivery to the lungs is partly due to CO2 losses into the dialysate, but mainly due to CO2 consumption during the metabolism of acetate [29]. There is no change in the alveolar-arterial P oxygen (02) gradient during dialysis, excluding changes in diffusion capacity [30]. The hypoxic

reaction is similar in adults with chronic obstructive pulmonary disease and those with healthy lungs. As the starting point of oxygenation is lower, patients with impaired pulmonary function experience a lower P 02 during dialysis. Marginally oxygenated patients should therefore receive supplementary 02 during dialysis [31]. In ventilated patients, if alveolar hypoventilation is avoided, hypoxaemia is not seen [32]. Due to the extrapulmonary CO2 losses, hypocarbia can arise if ventilator settings are not adjusted. In the post-dialysis period, oxygenation has to be monitored for several hours in patients with compromised lung function, as after both acetate and bicarbonate dialysis hypoxaemia can occur in these patients [31]. Hypoxia during peritoneal dialysis is mainly related to the increase in peritoneal pressure, diaphragmatic elevation with decreased vital capacity, diminished perfusion of the lung basal areas, atelectasis and an increase of transpulmonary pressure. These reversible changes are all produced by the introduction of greater dialysate volumes into the peritoneal cavity [33, 34]. They can be avoided by increasing the number of cycles with reduced dialysate volumes. Summarizing, PD if not contraindicated, is the least compromising procedure for intensive care patients. The different haemofiltration procedures with biocompatible membranes are attractive alternatives. If necessary, HD should be performed with bicarbonate.

Circulatory support The uraemic patient is at greater risk of developing circulatory shock than other patients (Table 1). In cardiovascular instability, dialysis-induced hypovolaemia can be prevented by the use of more appropriate techniques. In most

Table 1. Shockin uraemicpatients Classificationof shock Hypovolaemic dehydration haemorrhage burns Cardiogenic pericarditis cardiomyopathy myocardialdepression ischaemia arrhythmias Septic Distributive anaphylaxis neurological intoxication sepsis Other air embolism

dialysis-induced gastroenteritis, vomiting trauma, haematoma(heparinization!) gastrointestinal ulcers uraemic hypertension drugs (barbiturates) anoxia hyperkalaemia

drugs, vaccines,food,blood, insects, iodinecontrastmedia head trauma barbiturates, thiazides, antihypertensives,tranquilizers

90 cases, hypovolaemia can be managed by infusing crystalline solutions. More serious problems arise from post-traumatic haematoma aggravated under systemic heparinization. Even if the bleeding can be stopped with protamine and hypovolaemia treated by transfusions, the patient is at high risk of developing severe therapy-refractory hyperkalaemia if a giant haematoma develops. Cardiogenic shock can ensue from uraemic pericarditis, hypertensive cardiomyopathy or arrhythmias caused by hyperkalaemia. The risk of septic shock is increased. Today, air embolism should not occur during HD due to adequate equipment and elaborate techniques for blood reinfusion at the end of a dialysis session. Shock is a state of circulatory insufficiency with an inadequate blood supply and perfusion at the tissue level, myocardial and cerebral tissues being preserved longest. All shock states are explained by abnormalities of one or several of the following factors: blood volume, vascular tone or cardiac function. Treatment goals are: the optimization of perfusion in critical vascular regions of the myocardium and central nervous tissues, and the correction of hypoxic metabolic derangements. The procedures applied only then exhibit a sustained effect if the underlying disease is treated simultaneously. So the most effective therapeutic measure for hyperkalaemia-induced myocardial dysfunction is institution of immediate dialysis. Bicarbonate injections have a minimal effect on serum potassium levels in uraemia [35]. Insulin-glucose infusions carry the risk of hypoglycaemia because, as has been shown in uraemic adults, the counterregulatory hormonal responses of adrenocorticotropic hormone, cortisol and growth hormone to insulin-induced hypoglycaemia are reduced [36]. A relatively safe and efficient method of controlling serum potassium while preparing dialysis is the infusion of 4 gg/kg salbutamol over 20 min [37]. 02 delivery is a major goal in therapy. Patients who have suffered prolonged shock should be intubated and receive ventilatory support. If the respiratory insufficiency is aggravated by non-cardiogenic pulmonary oedema (adult respiratory distress syndrome), introduction of a positive-end expiratory pressure will improve oxygenation by normalizing the functional residual capacity and decreasing pulmonary shunting [38]. In absolute or relative hypovolaemia, a rapid intravascular volume expansion augments cardiac preload and restores blood pressure and peripheral perfusion. Usually a volume of 10-20 ml/kg within 10 rain is necessary. In the absence of underlying cardiac dysfunction, this will not result in pulmonary oedema. Whether crystalline or colloidal solutions should be used is still being debated. Colloid remains longer in the circulation and produces a more sustained effect on blood pressure. However, in septic shock this can also leak from the intravascular to the interstitial space. Since urinary output as a measure of restored intravascular volume is not seen in the child with renal failure, more invasive monitoring is required. If a volume of more than 5 0 - 6 0 ml/kg is needed within the first 4 - 6 h, or if there is any evidence of myocardial impairment, the central venous pressure (CVP, upper limit 10-12 mmHg) should be assessed. If an increase in CVP

does not correspond with a clinical improvement, monitoring of the pulmonary wedge pressure (upper limit 16-18 mmHg) using a pulmonary artery catheter is mandatory. Echocardiography is a reliable tool for assessing left ventricular performance. In anaemic patients, transfusion of packed red blood cells can improve O2 delivery by elevation of the O2-transporting capacity. Whether this also increases 02 consumption without increasing myocardial workload, the main goal of this approach, is controversial [39-41]. All these investigations were performed in septic shock, where distributional probtems and toxic myocardial dysfunction are of greater concern than in other diseases. With compromised renal function, serum potassium levels can increase with the transfusion [42]. ff pre-transfusion levels are critical, the use of washed red blood cells is preferred. In cardiogenic shock, inotropic support is required. Digitalis glycosides have the disadvantages of slow onset of action and long half-lives. Catecholamine metabolism has several peculiarities in uraemic patients, summarized by the term "autonomic neuropathy". In contrast to adults, however, uraemic children produce a normal catecholamine response to hypovolaemia [43]. In uraemia, dose adjustment of therapeutic catecholamines is unnecessary. The most frequently used catecholamines are: dopamine, dobutamine, epinephrine and norepinephrine. Although with the use of dopamine in low ( 1 - 3 gg/kg per rain) doses an increase in glomerular filtration rate in patients with advanced renal insufficiency does not occur, effective renal plasma flow and fractional sodium excretion increase [44, 45]. Thus, even in uraemia it still makes sense to add dopamine in a moderate dose to other catecholamines. Doses of 3 - 1 0 gg/kg per rain produce an inotropic effect; higher doses increase peripheral resistance and myocardial afterload. Dobutamine (1-20 gg/kg per min) is the major inotropic agent for resuscitation. It can, however, produce peripheral vasodilatation which may have a deleterious effect on myocardial performance. The main indication for epinephrine is cardiac arrest. The improvement in cardiac performance with continuous use (0.05-1.0 gg/kg per min) is achieved at the expense of an increase in cardiac O2 expenditure. Norepinephrine as a potent vasoconstrictor (0.05-1.0 mg/ kg per min) is mainly used in distributional shock. By increasing arterial pressure it can ensure myocardial perfusion pressure [46, 47]. In severe cardiogenic shock due to cardiomyopathy, or myocardial failure due to septic shock, a reduction of the left ventricular afterload is indicated. Sodium nitroprusside (0.5-10.0 gg/kg per rain) is a potent peripheral vasodilatot. Combination therapy with inotropic drugs is indicated in many of these situations. The kidneys of uraemic patients cannot compensate for shock-induced metabolic acidosis, even if their perfusion is restored. Hence a greater amount of buffer (Sodium bicarbonate or tromethamol) will be required. As bicarbonate causes a fall in serum ionized calcium when the pH returns to normal, problems can occur if the patient had low calcium levels initially. If metabolic acidosis is not controlled by these means, dialysis has to be instituted immediately after stabilization of the circulation. Regardless of whether

91 Table 2. Antibiotics where a dose adjustment for renal insufficiencyis not necessary.Adaptedfrom [54] and [55]

Table 3. Antibiotics where a dose adjustment for renal insufficiencyis

Cefoperazon Chloramphenicol Clindamycin Cloxacillin Erythromycin

Acyclovir Aminoglycosides Ampicillin,Amoxicillin Azlocillin Cefaclor Cefazolin Cefotaxime Cefsulodin Cephalothin Doxycycline Ethambutol Isoniazid Lincomycin MethiciUin Metronidazole Mezlocillin Moxalactam Penicillin G Piperacillin Sulphamethoxazole Trimethoprim Vancomycin Vidarabine

(H) (H)

Ketokonazole Miconazole Nafcillin Oxacillin (H,P) Rifampicin

H, Supplementary dose needed for haemodialysis; P, Supplementary dose needed for peritonealdialysis

HD or haemofiltration is used, in severe acidosis and cardiovascular instability bicarbonate and not lactate-containing solutions should be used [48]. PD may interfere with ventilatory support. Smaller and more frequent dwell volumes than usual should be used, although this may delay metabolic corrections.

I n f e c t i o n s a n d antibiotic t r e a t m e n t

lnvasive diagnostic and therapeutic procedures increase the chance of infection in all intensive care patients. If dialysis is required, the amount of invasive handling is further increased. The reasons for the increased risks of infection in uraemic patients are not fully understood. The results of clinical studies on the immunology and neutrophil or macrophage function in uraemic patients are conflicting, and were mostly obtained from adult patients. A recent study, performed on a limited number of paediatric patients with chronic renal failure, with or without renal replacement therapy, revealed no abnormalities in the percentages of B and T cells, T cell subpopulations, the mitogenic responses to phytohaemagglutinin and concanavalin A or immunoglobulin concentrations [49]. There are changes in neutrophil function during HD, especially if this is performed with less biocompatible membranes. This may increase the susceptibility to infection during dialysis [50]. PD fluids exert an inhibitory effect on neutrophil phagocytosis. This depends mainly on dialysis fluid osmolality, pH and lactate content. During PD the peritoneal cavity is depleted of leucocytes, opsonins and immunoglobulins, which enhances the susceptibility to infections [51-53]. In the treatment of infection, antibiotics have to be administered in doses adjusted to the degree of renal failure (Tables 2, 3) [54-59]. These recommendations can only be guidelines, which should be revised for individual patients. For potentially toxic agents, drug level monitoring is mandatory. Elimination during dialysis or haemofiltration is not well established for all drugs. Most dosage recommendations do not take into consideration the possible differences in dialysis technique, e.g. use of membranes of different permeability or the amount of ultraffltration. For instance, vancomycin clearance is doubled in machine haemofiltration compared with CAVH, as it is simply correlated to the ultrafiltration rate [60]. A supplementary dose of aminoglycosides is needed after HD. The elimination of amikacin is not increased during

mandatory.Adapted from [54, 55] (I) (I,D) (I) (I) (I) (I) (I) (D) (I) (I)a (I) (D)a (I) (I) (I) (I) (I) (I) (I) (I) (I) (I,D) (D)a

(H) (H,P)b (H) (H) (H) (H) (H) (H) (H,P) (H,P) (H) (H) (H) (H) (H) (H) (H) (H)

a Onlyin severerenal failure (glomerularfiltrationrate