Klein (1993, 1994) proposed an integrative model of panic disorder and agoraphobia that builds on the carbon dioxide hypersensitivity theory and incorporates clinical observations as well as experimental evidence. The carbon dioxide theory proposes that PD patients have a lower physiological threshold for detecting increased CO2 levels in the organism; therefore, even slight changes in the CO2 concentrations can trigger a panic attack.

Klein found this explanation too narrow and unable to explain many aspects of the PD. According to his theory, we acquired during our evolution a suffocation alarm system that monitors the levels of carbon dioxide and oxygen. When the ratio of these gazes reaches the suffocation threshold, the alarm goes on and sends a message advising us that there is a danger of suffocating. The normal and adaptive reaction is to escape from the place where the right ratio between the CO2 and O2 is not available.

Most people have such alarm reactions only when there is a real danger of suffocation. In PD patients, however, this alarm system is oversensitive and misfires after interpreting certain benign endogenous (inflammation of respiratory organs during a flu) or exogenous (being in a crowd) indices as a possible suffocation danger. The impression of breathlessness caused by a rapid increase in CO2 or by the chronically lowered suffocation threshold causes respiratory stimulation and hyperventilation. Hyperventilation leads to dizziness and paraesthesia. Other symptoms of panic follow as well as, a result of the activation of the sympathetic branch of the autonomic nervous system.

Klein makes a distinction between two basic groups of patients. The first group constitutes of patients who react most to lactate infusion and CO2 challenge. Those are the patients who have dyspnea as their predominant symptom, and who often chronically hyperventilate which leads to lowered suffocation threshold as a compensatory mechanism. The majority of agoraphobics comes from this category. The other group of patients is characterized by sporadic panic attacks, with palpitations, tachycardia, tremors and sweating as major symptoms. This group presents an increased vulnerability to challenges acting on the noradrenergic system, such as yohimbine, and beta-carbolines, rather than to lactate. In these patients, Klein argues, the activation of the hypothalamo-pituitary axis triggers the panic attack, and the suffocation threshold is not altered.