The effect of resuscitation fluids on beta lactam antibiotic pharmacokinetics in interstitial tissue in acute thermal injury

Kanchanamala Ranasinghe (2010). The effect of resuscitation fluids on beta lactam antibiotic pharmacokinetics in interstitial tissue in acute thermal injury PhD Thesis, School of Medicine, The University of Queensland.

       
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Author Kanchanamala Ranasinghe
Thesis Title The effect of resuscitation fluids on beta lactam antibiotic pharmacokinetics in interstitial tissue in acute thermal injury
School, Centre or Institute School of Medicine
Institution The University of Queensland
Publication date 2010-04-01
Thesis type PhD Thesis
Supervisor Prof Michael S Roberts
Prof Bala Venkatesh
Dr. Sheree Cross
Total pages 267
Total colour pages 15
Total black and white pages 252
Subjects 11 Medical and Health Sciences
Abstract/Summary Advantages and disadvantages of administration of resuscitation fluids in burns patients have been discussed at length. However, the effect of resuscitation fluids on tissue physiological endpoints and tissue antibiotic distribution is scarcely reported, yet clinically crucial. The preliminary studies of this thesis involved evaluation of the literature and the development of a non - recovery anaesthetized rat model of burn injury suitable for the study of plasma and tissue physiological changes and antibiotic pharmacokinetics (PK). Therefore, the first series of the studies for this thesis was designed to examine the relative effects of a range of crystalloid and colloid-containing resuscitation fluids on tissue pH following burn injury in a rat model. The secondary aims were to examine the effects of these fluids on tissue blood flow, plasma protein extravasation (PPE) and evaporative water loss (EWL). In these studies we confirmed that the burn injury and fluid resuscitation were accompanied by a tissue acidosis. Administration of Lactated Ringers’ Albumin (LRA) and Lactated Ringers’ Dextran (LRD) effectively attenuated the degree of tissue acidosis in the thermally injured and non injured sites for 180 minutes post burn and the transepidermal water loss (TEWL) on the non injured sites during the first 60 minutes of the acute phase of burn injury. The second phase of the work was designed to assess the changes in antibiotic distribution with the administration of these different fluids in plasma as well as in interstitial tissues in the burn and the non burn sites. This study showed that for cephalothin (4g/kg body weight, administered intravenously (IV)), Lactated Ringers solution (LR) and Hypertonic Saline (HS) showed similar plasma PK with Time > Minimum inhibitory concentration (MIC) (> 180 minutes) in plasma. However, the antibiotic tissue distribution was more skewed towards lower levels for HS when compared with LR. For piperacillin (18g/kg body weight, administered IV), Time > MIC was considerably low comparatively, being only 55 min for both LR and HS. Antibiotic concentrations did not reach the MIC with LRA resuscitation. When considering the interstitial tissues, Time > MIC for cephalothin was lower than HS with LR on both the burn and the non burn sites. T > MIC for piperacillin was zero for all fluids in both burn and non burn sites. The major finding of this study was that with LRA resuscitation, antibiotic distribution was significantly lower than seen with LR and HS for both antibiotics studied in the interstitial tissue fluid space in both the burn and non burn sites. The final phase of the work was designed to study the apparent permeability co efficient of Keratinocytes (KC) to antibiotics in the presence of simulated pH changes observed in burn tissue in thermal injury using colloids and crystalloids. This study found that there was no significant difference between the basolateral and apical concentrations of antibiotics observed neither with the different pH values nor with time. However, there was definitely a significant difference in the apparent permeability of the cells with LR vs LRA and that the permeability was higher with LR than LRA. This study confirmed that the presence of LR allows greater permeation of the antibiotic into the KC, and also that with LRA resuscitation, the antibiotic tends to stay at higher concentrations in the interstitial compartment. These studies demonstrate that choice of resuscitation fluid following burn injury can affect both changes in tissue physiology and antibiotic distribution, warranting further study in both animal models and patient populations.
Keyword Resuscitation fluids
Beta lactam antibiotics
Antibiotic pharmacokinetics
Pharmacodynamics
Microdialysis
Acute thermal injury
Additional Notes 55,69,84,139,140,141,159,171,174,178,186,191,192,208,211

 
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Created: Wed, 30 Jun 2010, 03:09:14 EST by Dr Kanchanamala Ranasinghe on behalf of Library - Information Access Service