**1.5.1 Acute therapy**

For main therapeutic recommendations, we follow the ESC 2008 guidelines (Torbicki et al., 2008). Anticoagulation therapy should be initiated upon suspicion of PE. 5000 IU Na-heparin is recommended as intravenous bolus if the patient had not already received Low Molecular Weight Heparin (LMWH) previously. Besides providing secure venous access, patients should receive immediate oxygen therapy through a 50% or 100% face mask. The indication of oxygen therapy is absolute, but mechanical ventilation should be used with caution. Mechanical ventilation may decrease the venous reflow and increases RV insufficiency, therefore, low tidal volume (7 ml/kg) ventilation and intravenous fluid therapy is recommended. The alveolar-arterial gas exchange can also be impaired as shunt-flow and cardiac output decrease (Singer, M; Webb, 2004; Sevransky et al., 2004). Capnometry is highly recommended during mechanical ventilation, as it may change due to thrombolysis

Pathophysiology, Diagnosis and Treatment of Pulmonary

al., 2008).

before TL.

**negative**

**No embolism, look for other cause**

**negative**

Embolism Focusing on Thrombolysis - New approaches 127

measured the effect of 600 ml crystalloid infusion and found an increase of cardiac index from 1.7 to 2.0 l/min/m2. Also, Mercat et al. found the same increase of cardiac index after the infusion of 500 ml dextrane. Modest fluid challenge is recommended, as fluid overload may depress contractility and decrease cardiac output (Kasper et al., 1997; Mercat et al., 1999; Ozier et al., 1984). If bronchospasm develops 200 mg intravenous theophyllin may be administered. If required, norepinephrine and/or dobutamine are the choice of positive inotropic drugs. Norepinephrine improve RV function with direct effect on contractility (Prewitt, 1990). Büchner primary recommends norepinephrine and dobutamine

Elevated lactate levels indicate capillary perfusion impairment. The normalisation of lactate shows the resolution of the haemodynamic failure. Also, a radial arterial line is useful for continuous blood pressure monitoring and to draw frequent blood samples upon the verification of high-risk or non high-risk PE. Pulse contour cardiac output systems, like the "PiCCO"-system (Pulsion Medical Inc., Germany) is capable of continuous haemodynamic monitoring including cardiac output. Phosphodiesterase-III inhibitors (i.e. enoximon) and Ca-channel sensitizers (i.e. levosimendan) may have a beneficial effect, but insufficient clinical evidence is available yet (Nowak et al., 2007; Kerbaul et al., 2007). Also, the inhalation of nitrous oxide may improve the gas exchange of patients with PE (Torbicki et

If deep vein Doppler ultrasound suspects a floating, weak structure clot, thus reembolisation may occur, a temporary placement of caval vein filter should be considered

> **Signs and symptoms of PE (blood gas, ECG etc.)**

> > **negative**

**positive positive**

**DVT US**

**Heparin/LMWH**

Fig. 5. The authors' own diagnostic and therapeutic approach (US: ultrasound)

**negative**

**D-dimer, troponin, BNP**

**positive**

**MDCT**  if not available: echocardiography or perfusion scan + chest X-ray

**positive + stable**

**echocardiography**

**positive (intermediate risk)**

**positive + shock** 

**caval filter? TL**

combination for haemodynamic shock (S. Büchner & Th. Hachenberg, 2005).

#### **High risk PE (Shock/hypotension)**

Fig. 3. The ESC 2008 guideline recommended diagnostic steps for high risk PE patients

**Non-high risk PE (without Shock or hypotension)**

Fig. 4. The ESC 2008 guideline recommended diagnostic steps for non-high risk PE patients

or re-embolism. Morphine (or other opiate analgesic) can be administered as repeated intravenous bolus of 2 mg for analgesia. To achieve optimal haemorheological parameters and a desirable volume state, aggressive fluid resuscitation must be carried out intravenously in the acute phase (crystalloid 1.5-2 ml/kg/h). Early fluid resuscitation is recommended based on hypotension from the loss of LV end diastolic volume. Ozier et al.

**High risk PE (Shock/hypotension)**

CT available, patient is stable **CT**

> **Specific PE treatment TL/Embolectomy**

positive negative

High probability of PE

**Multidetector CT**

negative **positive**

No PE treatment, look for other cause

**PE treatment**

Look for other cause, no thrombolysis needed.

**Urgent MDCT available?**

no yes

Fig. 3. The ESC 2008 guideline recommended diagnostic steps for high risk PE patients

**Non-high risk PE (without Shock or hypotension)**

**Look for clinical PE signs!**

Fig. 4. The ESC 2008 guideline recommended diagnostic steps for non-high risk PE patients or re-embolism. Morphine (or other opiate analgesic) can be administered as repeated intravenous bolus of 2 mg for analgesia. To achieve optimal haemorheological parameters and a desirable volume state, aggressive fluid resuscitation must be carried out intravenously in the acute phase (crystalloid 1.5-2 ml/kg/h). Early fluid resuscitation is recommended based on hypotension from the loss of LV end diastolic volume. Ozier et al.

**Echocardiography RV overload?**

no yes

Low probability of PE

**D-dimer**

negative **positive**

No PE treatment

> No PE treatment

**Multidetector CT**

negative **positive**

**PE treatment**

No other diagnostics available, or unstable patient

Look for other cause, no thrombolysis needed.

measured the effect of 600 ml crystalloid infusion and found an increase of cardiac index from 1.7 to 2.0 l/min/m2. Also, Mercat et al. found the same increase of cardiac index after the infusion of 500 ml dextrane. Modest fluid challenge is recommended, as fluid overload may depress contractility and decrease cardiac output (Kasper et al., 1997; Mercat et al., 1999; Ozier et al., 1984). If bronchospasm develops 200 mg intravenous theophyllin may be administered. If required, norepinephrine and/or dobutamine are the choice of positive inotropic drugs. Norepinephrine improve RV function with direct effect on contractility (Prewitt, 1990). Büchner primary recommends norepinephrine and dobutamine combination for haemodynamic shock (S. Büchner & Th. Hachenberg, 2005).

Elevated lactate levels indicate capillary perfusion impairment. The normalisation of lactate shows the resolution of the haemodynamic failure. Also, a radial arterial line is useful for continuous blood pressure monitoring and to draw frequent blood samples upon the verification of high-risk or non high-risk PE. Pulse contour cardiac output systems, like the "PiCCO"-system (Pulsion Medical Inc., Germany) is capable of continuous haemodynamic monitoring including cardiac output. Phosphodiesterase-III inhibitors (i.e. enoximon) and Ca-channel sensitizers (i.e. levosimendan) may have a beneficial effect, but insufficient clinical evidence is available yet (Nowak et al., 2007; Kerbaul et al., 2007). Also, the inhalation of nitrous oxide may improve the gas exchange of patients with PE (Torbicki et al., 2008).

If deep vein Doppler ultrasound suspects a floating, weak structure clot, thus reembolisation may occur, a temporary placement of caval vein filter should be considered before TL.

Fig. 5. The authors' own diagnostic and therapeutic approach (US: ultrasound)

Pathophysiology, Diagnosis and Treatment of Pulmonary

disorder or fibrinogen levels < 0.6 g/l (Mühl et al., 2007).

(aPTT) levels on admission) (Segal, Streiff, et al., 2007).

hirudin, lepirudin, danaparoid or fondaparinux.

**1.5.3 Catheter extraction and surgical embolectomy** 

2002; Goldhaber et al., 1993).

**1.5.4 Intravenous (caval) filter** 

2001).

heparin is adjusted to reach a target aPTT (Torbicki et al., 2008).

these scenarios.

Embolism Focusing on Thrombolysis - New approaches 129

Based on our previous clinical investigations, in case of bleeding complications the repetitive measurement of clot formation factors (namely fibrinogen and plasminogen) may indicate the need of specific factor replacement or fresh frozen plasma infusion during or following TL. Major bleeding complications can be reduced below 5%, if factor replacement takes place in patients with fibrinogen levels below 1.5 g/l accompanied by minor bleeding

Patients may not benefit from the TL of a more than 5-7 days old clot. Also, a second unsuccessful TL may indicate the presence of an older, connective tissue rich clot. Invasive radiology clot fragmentation and removal with or without selective TL should be used in

*Anticoagulation therapy during TL:* In the rt-PA group unfractionated heparin is recommended during TL (500-1000 IU/h, based on actual partial thromboplastin time

*Anticoagulation therapy after TL:* Anticoagulant therapy starts after strepto- or urokinase TL with intravenous unfractionated heparin to maintain aPTT (check every 4 hours!) between 50-70 seconds for the first 48 hours and continues with a therapeutic dose of LMWH, if no further TL cycle is necessary. Using the "Heparin adjustment nomogram", the dose of Na-

Anticoagulant therapy should be provided with intravenous unfractionated heparin to maintain the aPTT between 60-70 seconds for 48 hours. If TL was effective it should be continued with a therapeutic dose of LMWH. Following TL, long term anticoagulation (acenocoumarol or warfarin) can start on day 3 or 4 (Torbicki et al., 2008; Kearon et al., 2008). In case of unfractioned heparin use, the incidence of HIT is 1-3% (about 1% with LMWH), therefore regular platelet count check is recommended (Greinacher, 2009; Morris et al., 2007). In case of confirmed HIT, one should switch from heparin/LMWH therapy to:

One of the most common complication of TL is minor bleeding (arterial/venous port bleeding, haematuria, suffusions, e.t.c.), major bleeding occurs in 13% of cases. The incidence of intracranial haemorrhage is 1.8% (Spöhr et al., 2005), (Konstantinides et al.,

Indications of percutaneous catheter embolectomy and fragmentation are unsuccessful systemic TL, contraindicatons of systemic lysis, PE with haemodynamic shock (resuscitation, mechanical ventilation), clot in the right heart, and also an alternative for the surgical embolectomy if no experienced team is available (Kucher et al., 2005; Uflacker,

Surgical embolectomy has a high mortality rate in the high-risk PE group. Indications are narrow, only patients with absolute systemic TL contraindications and in the absence of consent for TL may benefit from surgical intervention (Meneveau et al., 2006). Previous unsuccessful TL is not a contraindication for surgical embolectomy (Aklog et al., 2002).

Statistically there is no firm evidence of improved 12 days mortality of the caval filter use. Transient caval filters may be used up to 14 days. Late complications include migration and device thrombosis. Indications are not general; the main indication is suspected
