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The occurrence of acidosis following trauma or other clinical conditions that require large volumes of resuscitation fluid may be modified by manipulation of the physical chemistry properties of substances within plasma. These include the strong ion difference, modification of hydrogen ion production through control of alveolar ventilation, and protection/provision of protein and phosphate-based weak acids. An understanding of these principles as an alternative method to analyze/anticipate acid-base abnormalities is important during resuscitation. Loss of protein-based weak acids may often occur after trauma or other conditions requiring large-volume resuscitation. These losses may potentially be replaced with albumin-based colloid solutions. Large quantities of normal saline should be avoided so as to avoid hyperchloremia-induced metabolic acidosis. Ringer's lactate solution is preferred. Alveolar ventilation must be adjusted so as to eliminate further hydrogen ion production caused by hypercarbia. The serum base excess and/or hyperlactemia have only limited value in diagnosing acidosis and guiding resuscitation. Current experimental data and reviews of this topic were obtained from a Medline literature search. In addition, the personal experience and investigations of the authors in critically ill and injured patients were used to formulate recommendations.