Ultrafiltration and Backfiltration during Hemodialysis

Abstract: Ultrafiltration is the pressure-driven process by which hemodialysis removes excess fluid from renal failure patients. Despite substantial improvements in hemodialysis technology, three significant problems related to ultrafiltration remain: ultrafiltration volume control, ultrafiltration rate control, and backfiltration. Ultrafiltration volume control is complicated by the effects of plasma protein adsorption, hematocrit, and coagulation parameters on membrane performance. Furthermore, previously developed equations relating the ultrafiltration rate and the transmembrane pressure are not applicable to high-flux dialyzers, high blood flow rates, and erythropoietin therapy. Regulation of the ultrafiltration rate to avoid hypotension, cramps and other intradialytic complications is complicated by inaccurate estimates of dry weight and patient-to-patient differences in vascular refilling rates. Continuous monitoring of circulating blood volume during hemodialysis may enable a better understanding of the role of blood volume in triggering intradialytic symptoms and allow determination of optimal ultrafiltration rate profiles for hemodialysis. Backfiltration can occur as a direct result of ultrafiltration control and results in transport of bacterial products from dialysate to blood. By examining these problems from an engineering perspective, the authors hope to clarify what can and cannot be prevented by understanding and manipulating the fluid dynamics of ultrafiltration.     

Accidental Metabolic Acidosis during Hemodialysis

Abstract: Three incidents of metabolic acidosis during hemodialysis in 3 different patients are presented. Two patients became severely ill but recovered completely after treatment. In the third patient, the event was recognized before the acidosis became symptomatic. In all cases the acidosis was caused by an unbalanced supply of acidic dialysis concentrate. Two events were caused by mistaking acidic dialysis concentrate for acetate. In the third patient, the supply line from the bicarbonate concentrate jug was broken. The conductivity cell alarm was not activated during any of the incidents and in only 1 case during reconstruction of the accidents. The efficacy and safety of the conductivity cell alarm system regarding prevention of acid/base disturbances during hemodialysis are discussed.     

Gentamicin Pharmacokinetics and Pharmacodynamics during Short-Daily Hemodialysis

Background/Aims: Gentamicin pharmacokinetics have not been described in patients undergoing short-daily hemodialysis (SDHD). The aim of this study is to describe gentamicin pharmacokinetics and dialytic clearance (Cl(dial)) in SDHD patients and simulate gentamicin exposure after six dosing regimens to help guide future dosing. Methods: Six anuric patients undergoing SDHD were enrolled. Patients received intravenous infusion of 2 mg/kg gentamicin on day 1 after the first HD session followed by HD sessions on days 2, 3, and 4. Blood samples for determination of gentamicin concentrations were serially collected. Gentamicin pharmacokinetic parameters and Cl(dial) and interindividual variability terms (IIV) were estimated using NONMEM VII. Influence of patient weight on systemic clearance (Cl(s)) and central volume of distribution (V(c)) and influence of urea removal estimates on Cl(dial) were assessed. The model was used to simulate gentamicin concentrations after six dosing regimens including pre- and postdialysis as well as daily and every-other-day dosing. Results: A two-compartment model with first-order elimination from central compartment described gentamicin pharmacokinetics. Population estimates for Cl(s) and Cl(dial) were 7.6 and 134 ml/min, respectively. Patient weight was statistically significantly associated with Cl(s) and V(c). Predialysis every-other-day regimens were as effective (C(max) ≥8 mg/l and AUC(48 h) ≥140 mg·h/l) and less toxic (C(min) <2 mg/l and AUC(48 h) <240 mg·h/l) than postdialysis regimens. Conclusions: Estimated gentamicin Cl(dial) is higher than previous estimates with thrice-weekly regimens. Predialysis every-other-day dosing may be recommended during SDHD.     

Endogenous Bradykinin Contributes to Increased Plasminogen Activator Inhibitor 1 Antigen following Hemodialysis

Oxidative stress and inflammation predict cardiovascular events in chronic hemodialysis patients. Hemodialysis activates the kallikrein-kinin system, increasing bradykinin. Bradykinin promotes inflammation but also stimulates endothelial release of tissue-plasminogen activator and inhibits platelet aggregation. Understanding the detrimental and beneficial effects of endogenous bradykinin during hemodialysis has implications for the treatment of cardiovascular disease in the hemodialysis population. To test the hypothesis that bradykinin contributes to the inflammatory and fibrinolytic responses to dialysis, we conducted a double-blind, randomized, placebo-controlled crossover study comparing the effect of the bradykinin B₂ receptor blocker HOE-140 with vehicle on markers of oxidative stress, inflammation, fibrinolysis, and coagulation in nine hemodialysis patients without coronary artery disease. Bradykinin receptor antagonism did not affect the mean arterial pressure or heart rate response to dialysis. Monocyte chemoattractant protein 1 (MCP-1) peaked postdialysis; HOE-140 blunted the increase in MCP-1 (5.9 ± 5.9 versus 25.6 ± 20.1 pg/ml, P = 0.01). HOE-140 also abolished the increase in plasminogen activator inhibitor 1 (PAI-1) antigen observed at the end of dialysis. In contrast, HOE-140 significantly accentuated the effect of dialysis on F₂-isoprostanes and P-selectin. Taken together, these results suggest that endogenous bradykinin contributes to increases in MCP-1 and PAI-1 antigen after hemodialysis via its B₂ receptor. Factors that increase the production of bradykinin or decrease its degradation may enhance the inflammatory response to hemodialysis.ESRD patients face a 3.4-fold risk of cardiovascular events compared with the general population,¹ and chronic hemodialysis (CHD) patients face a 100-fold higher risk of cardiovascular death compared with the general population in patients age 45 yr or younger.² Traditional risk factors for atherosclerosis do not account for the increased incidence of cardiovascular events.³ On the other hand, biomarkers of oxidative stress and inflammation predict cardiovascular events in CHD patients.^2,4During hemodialysis, contact of the blood with the dialyzer and dialysate activates the kallikrein-kinin system (KKS) and induces a systemic inflammatory response characterized by complement activation, leukocyte activation, and the generation of cytokines.⁵ For example, hemodialysis increases leukocyte expression of interleukin (IL)-1β, IL-8, and TNF-α, and circulating concentrations of IL-6.^6,7 Increased inflammation may, in turn, contribute to derangements of the fibrinolytic system in CHD patients. Cytokines such as TNF-α, IL-1β, and IL-6 stimulate expression of plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of fibrinolysis in vivo.⁸ Tissue-type plasminogen activator (t-PA) concentrations and activity increase transiently during hemodialysis, whereas circulating PAI-1 concentrations are increased in the CHD population.^9–11Activation of the KKS during hemodialysis could have favorable or deleterious effects on inflammation and the risk of cardiovascular events. On the one hand, bradykinin causes vasodilation and stimulates the release of t-PA from the vascular endothelium via bradykinin B₂ receptor-dependent mechanisms, and infused bradykinin inhibits platelet aggregation in healthy subjects.^12–14 On the other hand, bradykinin also stimulates activation of nuclear factor κB and cytokine expression via the B₂ receptor.^15,16 Understanding the contribution of endogenous bradykinin to the inflammatory response to hemodialysis has important implications for the prevention of atherothrombotic events.Specifically, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) decrease mortality in patients at risk for cardiovascular events in the general population,^17,18 but studies in the CHD population provide conflicting data and often do not discriminate between the effects of ACE inhibitors and ARBs.^19–22 The only prospective, randomized clinical trial did not show a beneficial effect of ACE inhibition in patients undergoing hemodialysis.²³ Whereas ACE inhibitors and ARBs decrease angiotensin II formation or action, ACE inhibitors also potentiate the effects of bradykinin.^24–26 Indeed, during hemodialysis with a polysulfone membrane, plasma bradykinin concentrations are higher during treatment with an ACE inhibitor compared with during treatment with an ARB.²⁷ In light of differences in mechanism of action between ACE inhibitors and ARBs, understanding the contribution of endogenous bradykinin to the proinflammatory effects of hemodialysis could affect the use of these agents in the CHD population.This study tested the hypothesis that activation of the KKS and the formation of endogenous bradykinin contribute to hypotension, increased inflammation, increased oxidative stress, and increased fibrinolysis in response to hemodialysis. To accomplish this, we compared the effect of continuous infusion of the bradykinin B₂ receptor-specific antagonist HOE-140 versus vehicle on the acute responses to hemodialysis.     

Endobronchial Vasopressin Improves Survival during Cardiopulmonary Resuscitation in Pigs

Background: Intravenous administration of vasopressin during cardiopulmonary resuscitation (CPR) has been shown to be more effective than optimal doses of epinephrine. This study evaluated the effect of endobronchial vasopressin during CPR.

Methods: After 4 min of untreated ventricular fibrillation and 3 min of CPR, 21 pigs were randomized to be treated with 0.8 U/kg intravenous vasopressin (n = 7), 0.8 U/kg endobronchial vasopressin (n = 9), or an endobronchial placebo of normal saline (n = 5). Defibrillation was performed 5 min after drug administration to attempt return of spontaneous circulation.

Results: All animals in the intravenous and endobronchial vasopressin group were resuscitated successfully, but only two of five animals in the placebo group were. At 2 and 5 min after drug administration, coronary perfusion pressure in the intravenous and endobronchial vasopressin group was significantly higher than in the placebo group (50 +/- 10, 34 +/- 5 vs. 16 +/- 6 mmHg, respectively; and 35 +/- 10, 39 +/- 10 vs. 19 +/- 5 mmHg, respectively; P < 0.05).     

Vasopressin and oxytocin release during prolonged environmental hypoxia in the rat

BACKGROUND: The mechanism causing peripheral oedema in hypoxaemic chronic obstructive pulmonary disease has not been established. Vasopressin, a powerful antidiuretic hormone involved in salt and water homeostasis, is released in response to acute hypoxia. However, the effect of prolonged hypoxaemia on hypothalamic and pituitary release of the magnocellular hypothalamic hormones, vasopressin and oxytocin, has not previously been studied. METHODS: Male Wistar rats were randomly allocated to either normobaric, hypoxic (10% O2) or control (21% O2) environmental chambers. An initial series of experiments examined plasma vasopressin concentration, osmolality, sodium concentration, packed cell volume (PCV), and weight gain at weekly intervals (n = 4-6) for six weeks. The maximum increase in plasma vasopressin concentration and PCV occurred after five weeks. In a second experiment vasopressin and oxytocin concentrations in the hypothalamus, pituitary gland, and plasma were measured in eight control and eight hypoxic rats after five weeks in the environmental chambers. RESULTS: In rats exposed to environmental hypoxia PCV increased (p < 0.001) and weight gain decreased (p < 0.05) compared with controls. The plasma vasopressin concentration increased progressively from a baseline of 1.36 (0.2) pmol/l (n = 6) to a maximum of 4.38 (0.8) pmol/l (n = 6; p < 0.01) during the first five weeks of environmental hypoxia (difference 3.02 (95% CI 1.18 to 4.86)). Plasma osmolality and sodium concentration were unchanged in hypoxic rats compared with controls during the six week period. The hypothalamic vasopressin concentration was increased (p < 0.001) after five weeks of environmental hypoxia (91.6 (4.8) pmol/ hypothalamus) compared with controls (57.4 (5.1) pmol/hypothalamus), the difference being 34.2 pmol/hypothalamus (95% CI 21.6 to 46.5). The pituitary vasopressin concentration was unchanged. In hypoxic rats hypothalamic oxytocin (59.6 (3.2) pmol/hypothalamus) was greater (p < 0.01) than in controls (42 (3.8) pmol/hypothalamus), a difference of 17.6 pmol/ hypothalamus (95% CI 8.7 to 26.5). Similarly, the plasma oxytocin concentration was increased (p < 0.05) in hypoxic rats (6.78 (1.2) pmol/l) compared with controls (3.3 (0.8) pmol/l), a difference of 3.48 pmol/l (95% CI 0.89 to 6.07). The pituitary oxytocin concentration was unchanged in the two groups. CONCLUSIONS: These results demonstrate an increase in hypothalamic production of vasopressin and oxytocin in rats during prolonged hypoxaemia. Increased plasma concentrations of neurohypophysial hormones would be expected to impair sodium and water homeostasis in patients with hypoxaemia. However, the absence of change in the plasma osmolality and sodium concentrations in this study and previous clinical investigations suggests that compensatory mechanisms modulate the actions of both vasopressin and oxytocin. A reduction in renal blood flow or decreased renal responsiveness to the neurohypophyseal hormones may be involved.


     

Bulk Mass Transport Limitations during High-Flux Hemodialysis

Abstract: Solute clearance during high-flux hemodialysis is determined by the combined effects of solute convection and diffusion in the membrane, blood, and dialysate. Previous studies have focused almost entirely on the membrane transport phenomena, largely ignoring the potential contribution from bulk mass transport across the fluid boundary layers in the blood and dialysate. This study presents a theoretical analysis of the coupled transport equations in the membrane, blood, and dialysate including the contributions from both convective and diffusive transport in each of these regions. The resulting theoretical expression for the solute flux demonstrates that bulk mass transfer limitations can have an important effect on solute transport and, in turn, solute clearance during high-flux hemodialysis.     

Factors Which Affect Cardiac Performance during Hemodialysis

Cardiac performance during hemodialysis is dependent on preexisting conditions (i.e., coronary artery disease, myocardial hypertrophy, LV compliance, anemia, hypertension, etc.) and the hemodynamic alterations caused by the dialysis procedure itself (osmotic shifts, ionized calcium changes, etc.). Clinical hemodynamic investigations of cardiac performance during uremia have been hampered by the difficulty in isolating individual parameters of ventricular function. Myocardial reserve in dialysis patients is often reduced because of antecedent ischemic disease, hypertension, and the presence of autonomic dysfunction in many patients. Rapid volume losses or gains are likely to be less well tolerated with resultant hypotensive syndromes or pulmonary edema as the result. The controlled volume loss achievable with newer dialysis machines, the use of higher dialysate sodium concentrations, and the wider availability of erythropoietin may improve the tolerance to the procedure for many patients.     

Beneficial Effects of Short-term Vasopressin Infusion during Severe Septic Shock

Background: Septic shock is associated with vasopressin deficiency and a hypersensitivity to its exogenous administration. The goal of the current study was to determine whether short-term vasopressin infusion in patients experiencing severe septic shock has a vasopressor sparing effect while maintaining hemodynamic stability and adequate end-organ perfusion.

Methods: Patients experiencing septic shock that required high-dose vasopressor support were randomized to a double-blinded 4-h infusion of either norepinephrine (n = 11) or vasopressin (n = 13), and open-label vasopressors were titrated to maintain blood pressure. To assess end-organ perfusion, urine output and creatinine clearance, gastric mucosal carbon dioxide tension, and electrocardiogram ST segment position were measured.

Results: Patients randomized to norepinephrine went from a median prestudy norepinephrine infusion of 20.0 [mu]g/min to a blinded infusion of 17.0 [mu]g/min at 4 h, whereas those randomized to vasopressin went from a median prestudy norepinephrine infusion of 25.0 [mu]g/min to 5.3 [mu]g/min at 4 h (P < 0.001). Mean arterial pressure and cardiac index were maintained in both groups. Urine output did not change in the norepinephrine group (median, 25 to 15 ml/h) but increased substantially in the vasopressin group (median, 32.5 to 65 ml/h;P < 0.05). Similarly, creatinine clearance did not change in the norepinephrine group but increased by 75% in the vasopressin group (P < 0.05). Gastric mucosal carbon dioxide tension and electrocardiogram ST segments did not change significantly in either group.     

Exogenous and Endogenous Nitric Oxide but Not iNOS Inhibition Improves Function and Survival of Ischemically Injured Livers

The role of nitric oxide (NO) in liver ischemia/reperfusion I/R) injury remains controversial and few works have shed more information regarding the effect of exogenous (EX) and/or endogenous NO (EN) under conditions of I/R of the liver. We investigated the role of exogenous and endogenous NO and inducible nitric oxide synthase (iNOS) inhibition in liver function, neutrophil infiltration, and animal survival after liver I/R. Sprague-Dawley rats were subjected to total hepatic ischemia for 90 min using an extracorporeal porto-systemic shunt. The animals were divided into five groups, including the sham porto-systemic shunt with no ischemia, the control ischemic group, the L-arginine-treated group, the sodium nitroprusside (SNP or NaNP)-treated group, and the L- N 6 -(1-iminoethyl) lysine hydrochloride (L-NIL) (selective iNOS inhibitor)-treated group. The animal survival was followed for 7 days. Liver injury tests, tissue myeloperoxidase (MPO), and histology were analyzed at 6 h postreperfusion. L-Arginine- and sodium nitroprusside-treated groups demonstrated significant improvement in 7 days survival in comparison to the control (20%) ( p < .05). The best overall survival was obtained with SNP (70%), followed by survival in the L-arginine treated group (60%). The iNOS inhibitor group (40%) did not show any statistical significance when compared to the control group ( p > .05). Liver injury tests and histology scores in the SNP- and L-arginine-treated groups showed significant improvement when compared to the control group ( p < .01 and p < .05, respectively). The iNOS group demonstrated only a slight improvement in these parameters. The liver MPO (as a measurement of neutrophil migration into the liver parenchyma) was significantly decreased only in the SNP and L-arginine groups ( p < .05) but not in the iNOS group ( p > .5). We conclude that NO exogenous donors and substrates for the endogenous pathway are beneficial for the liver after severe I/R and could be important therapeutic targets to prevent damage following this phenomenon.